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1. Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations

Author

Ronald C. Petersen, Ana Graf, Chris Brady, Susan De Santi, Hana Florian, Jaren Landen, Mike Pontecorvo, Christopher Randolph, Kaycee M. Sink, Maria C. Carrillo, and Christopher J. Weber

Subjects
Alzheimer's disease, amyloid, biomarkers, clinical trials, cognition, cognitive impairment, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Alzheimer's disease (AD) staging criteria lack standardized, empirical description. Well‐defined AD staging criteria are an important consideration in protocol design, influencing a more standardized inclusion/exclusion criteria and defining what constitutes meaningful differentiation among the stages. However, many trials are being designed on the basis of biomarker features and the two need to be coordinated. The Alzheimer's Association Research Roundtable (AARR) Spring 2021 meeting discussed the implementation of preclinical AD staging criteria, and provided recommendations for how they may best be incorporated into clinical trials research. Discussion also included what currently available tools for global clinical trials may best define populations in preclinical AD trials, and if are we able to differentiate preclinical from clinical stages of the disease. Well‐defined AD staging criteria are key to improving early detection, diagnostics, clinical trial enrollment, and identifying statistically significant clinical changes, and researchers discussed how emerging blood biomarkers may help with more efficient screening in preclinical stages.

Published
2023
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2. 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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3. Computer simulations for assessing cognitively intensive instrumental activities of daily living in older adults

Author

Stephen R. Rapp, Ryan T. Barnard, Kaycee M. Sink, Dana G. Chamberlain, Valerie Wilson, Lingyi Lu, and Edward H. Ip

Subjects
Cognitive impairment, Assessment, Computer, Simulation, Validation, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction Aim is to evaluate validity, reliability, diagnostic precision, and user acceptability of computer simulations of cognitively demanding tasks when administered to older adults with and without cognitive impairment. Methods Five simulation modules were administered to 161 individuals aged ≥60 years with no cognitive impairment (N = 81), mild cognitive impairment (N = 52), or dementia (N = 28). Groups were compared on total accuracy and time to complete the tasks (seconds). Receiver operating characteristics were evaluated. Reliability was assessed over one month. Participants rated face validity and acceptability. Results Total accuracy (P

Published
2018
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4. Changes in metabolic risk factors over 10 years and their associations with late‐life cognitive performance: The Multi‐Ethnic Study of Atherosclerosis

Author

Timothy M. Hughes, Suzanne Craft, Laura D. Baker, Mark A. Espeland, Stephen R. Rapp, Kaycee M. Sink, Alain G. Bertoni, Gregory L. Burke, Rebecca F. Gottesman, Erin D. Michos, José A. Luchsinger, Annette L. Fitzpatrick, and Kathleen M. Hayden

Subjects
Metabolism, Metabolic disorders, Cognitive function, Brain, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background We examined whether changes in metabolic factors over 10 years were associated with cognitive performance. Methods Participants from the Multi‐Ethnic Study of Atherosclerosis were followed since baseline (2000–2002) with five clinical examinations. At exam 5 (2010–2012), they received a short cognitive battery (Cognitive Abilities Screening Instrument [CASI], Digit Symbol Coding [DSC], and Digit Span [DS]). We examined associations between baseline metabolic factors and their changes over time before cognitive testing. Results Among 4392 participants, baseline metabolic disorders (fasting glucose, systolic and diastolic blood pressures) were significantly associated with poorer CASI, DSC, and DS scores measured 10 years later. Increases in blood pressure were associated with lower cognitive performance. Results did not differ by race/ethnicity and were stronger among those without the APOE ε4 allele. Conclusions Cognitive performance was associated with antecedent abnormalities in glucose metabolism and blood pressure increases. Findings appeared stronger among APOE ε4‐negative participants.

Published
2017
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5. 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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6. 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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7. 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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8. 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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9. 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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10. Community-Based Activity and Sedentary Patterns Are Associated With Cognitive Performance in Mobility-Limited Older Adults

Author

Amal A. Wanigatunga, Todd M. Manini, Delilah R. Cook, Jeffrey Katula, Roger A. Fielding, Arthur F. Kramer, Joe Verghese, Stephen R. Rapp, Kaycee M. Sink, Abby C. King, Thomas W. Buford, Steve Anton, Neelesh Nadkarni, Janine M. Jennings, Kieran Reid, Mark A. Espeland, Thomas M. Gill, Marco Pahor, and Joe R. Nocera

Subjects
accelerometer, wearables, executive function, cognition, aging, physical inactivity, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Over the last few decades, considerable evidence shows that greater levels of aerobic exercise and cardiovascular fitness benefit cognitive performance. However, the degree to which free-living activity in community settings is related to cognitive performance remains unclear, particularly in older adults vulnerable to disability. Also, it is unknown whether the manner in which daily physical activity (PA) and sedentary time are accumulated throughout the day is associated with cognition. Cross-sectional associations between accelerometer-characterized PA and sedentary patterns and cognitive performance were examined in 1,274 mobility-limited older adults. Percent time spent in various bout lengths of PA (≥1, ≥2, and ≥5 min) and sedentary (≥1, ≥30, and ≥60 min) was defined as the number of minutes registered divided by total wear time × 100. Percent time was then tertiled for each bout length. Multiple linear regression models were used to estimate the associations between accelerometer bout variables and separate cognitive domains that included processing speed (Digit Symbol Coding; DSC), immediate and delayed recall (Hopkins Verbal Learning Test; HVLT), information processing and selective attention (Flanker), working memory (n-back), reaction time (switch and non-switch reaction time), and a composite score that averaged results from all cognitive tests. After adjusting for demographics, behavioral factors, and morbid conditions, more time spent in PA was associated with higher DSC for all bout lengths (p < 0.03 for all). Higher PA was associated with higher HVLT and global cognition scores but only for longer bout lengths (p < 0.05 for all). The association was largely driven by participants who spent the lowest amount of time performing activity while awake (p < 0.04). An inverse linear relationship was observed between total sedentary time and DSC (p = 0.02), but not for other measures of cognition. These results suggest that, while higher PA was associated with higher cognitive performance, PA’s association with memory was sensitive to bout duration. The time, but not the manner, spent in sedentary behaviors showed a minor association with executive function. Further research is warranted to characterize longitudinal changes in daily activity and sedentary patterns as potential biophysical markers of cognitive status in older adults.

Published
2018
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11. 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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12. 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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13. Montreal Cognitive Assessment and Modified Mini Mental State Examination in African Americans

Author

Kaycee M. Sink, Suzanne Craft, S. Carrie Smith, Joseph A. Maldjian, Donald W. Bowden, Jianzhao Xu, Barry I. Freedman, and Jasmin Divers

Subjects
Geriatrics, RC952-954.6
Abstract

Background. Sparse data limit the interpretation of Montreal Cognitive Assessment (MoCA) scores, particularly in minority populations. Additionally, there are no published data on how MoCA scores compare to the widely used Modified Mini Mental State Examination (3MSE). We provide performance data on the MoCA in a large cohort of African Americans and compare 3MSE and MoCA scores, providing a “crosswalk” for interpreting scores. Methods. Five hundred and thirty African Americans with type 2 diabetes were enrolled in African American-Diabetes Heart Study-MIND, a cross-sectional study of cognition and structural and functional brain imaging. After excluding participants with possible cognitive impairment (n=115), mean (SD) MoCA and 3MSE scores are presented stratified by age and education. Results. Participant mean age was 58.2 years (range: 35-83); 61% were female; and 64.9% had >12 years of education. Mean (SD) 3MSE and MoCA scores were 86.9 (8.2) and 19.8 (3.8), respectively. 93.5% of the cohort had a “positive” screen on the MoCA, scoring

Published
2015
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14. Intraindividual Variability in Domain-Specific Cognition and Risk of Mild Cognitive Impairment and Dementia

Author

Leslie Vaughan, Iris Leng, Dale Dagenbach, Susan M. Resnick, Stephen R. Rapp, Janine M. Jennings, Robert L. Brunner, Sean L. Simpson, Daniel P. Beavers, Laura H. Coker, Sarah A. Gaussoin, Kaycee M. Sink, and Mark A. Espeland

Subjects
Geriatrics, RC952-954.6
Abstract

Intraindividual variability among cognitive domains may predict dementia independently of interindividual differences in cognition. A multidomain cognitive battery was administered to 2305 older adult women (mean age 74 years) enrolled in an ancillary study of the Women’s Health Initiative. Women were evaluated annually for probable dementia and mild cognitive impairment (MCI) for an average of 5.3 years using a standardized protocol. Proportional hazards regression showed that lower baseline domain-specific cognitive scores significantly predicted MCI (N=74), probable dementia (N=45), and MCI or probable dementia combined (N=101) and that verbal and figural memory predicted each outcome independently of all other cognitive domains. The baseline intraindividual standard deviation across test scores (IAV Cognitive Domains) significantly predicted probable dementia and this effect was attenuated by interindividual differences in verbal episodic memory. Slope increases in IAV Cognitive Domains across measurement occasions (IAV Time) explained additional risk for MCI and MCI or probable dementia, beyond that accounted for by interindividual differences in multiple cognitive measures, but risk for probable dementia was attenuated by mean decreases in verbal episodic memory slope. These findings demonstrate that within-person variability across cognitive domains both at baseline and longitudinally independently accounts for risk of cognitive impairment and dementia in support of the predictive utility of within-person variability.

Published
2013
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15. Sex differences in cognitive resilience in preclinical autosomal‐dominant Alzheimer's disease carriers and non‐carriers: Baseline findings from the API ADAD Colombia Trial

Author

Clara, Vila-Castelar, Pierre N, Tariot, Kaycee M, Sink, David, Clayton, Jessica B, Langbaum, Ronald G, Thomas, Yinghua, Chen, Yi, Su, Kewei, Chen, Nan, Hu, Margarita, Giraldo-Chica, Carlos, Tobón, Natalia, Acosta-Baena, Ernesto, Luna, Marisol, Londoño, Paula, Ospina, Victoria, Tirado, Claudia, Muñoz, Eliana, Henao, Yamile, Bocanegra, Sergio, Alvarez, Silvia, Rios-Romenets, Valentina, Ghisays, Dhruman, Goradia, Wendy, Lee, Ji, Luo, Michael H, Malek-Ahmadi, Hillary D, Protas, Francisco, Lopera, Eric M, Reiman, and Yakeel T, Quiroz

Subjects
Adult, Male, Sex Characteristics, Epidemiology, Health Policy, Middle Aged, Colombia, Neuropsychological Tests, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Cognition, Developmental Neuroscience, Alzheimer Disease, Presenilin-1, Humans, Female, Neurology (clinical), Geriatrics and Gerontology
Abstract

Females may have greater susceptibility to Alzheimer's disease (AD)-pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively-unimpaired Presenilin-1 (PSEN1) E280A mutation carriers and non-carriers.We analyzed baseline data from 167 mutation carriers and 75 non-carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir- and fludeoxyglucose-PET, MRI based hippocampal volume and cognitive testing.Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory.Our findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex-specific differences in autosomal-dominant AD is key to elucidating mechanisms of AD risk and resilience.

Published
2022

16. Reproductive health data and its relationship to baseline brain imaging and cognitive measurements in cognitively unimpaired female PSEN1 E280A mutation carriers and non‐carriers from the API ADAD Trial

Author

Valentina Ghisays, Clara Vila‐Castelar, Margarita Giraldo‐Chica, Natalia Acosta‐Baena, Hillary D. Protas, Michael H. Malek‐Ahmadi, Yinghua Chen, Ji Luo, Wendy Lee, Yamile Bocanegra, Claudia Muñoz, Karina Herrera, Nan Hu, Kaycee M. Sink, David Clayton, Sergio Alvarez, Jessica B. Langbaum, Kewei Chen, Yi Su, Pierre N. Tariot, Yakeel T. Quiroz, Francisco Lopera, Eric M. Reiman, Silvia Ríos‐Romenets, and API ADAD Colombia Trial Group

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

17. Clinical Profiles of Persons Who Progress to Cognitive Impairment in the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial

Author

Margarita Giraldo‐Chica, Natalia Acosta‐Baena, Alejandro Espinosa, Claudia Ramos, Jessica B. Langbaum, Kaycee M. Sink, Pierre N. Tariot, Eric M. Reiman, Francisco Lopera, and Silvia Ríos‐Romenets

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

18. API ADAD Colombia Trial initial findings: a randomized, double‐blind, placebo‐controlled, parallel‐ group study in cognitively unimpaired PSEN1 E280A mutation carriers evaluating efficacy and safety of crenezumab

Author

Kaycee M. Sink, Rachelle S. Doody, Silvia Ríos‐Romenets, Pierre N. Tariot, Eric M. Reiman, and Jessica B. Langbaum

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

19. Robust demographically-adjusted normative data for the Montreal Cognitive Assessment (MoCA): Results from the systolic blood pressure intervention trial

Author

Linda O. Nichols, Tanya R. Gure, Jeff D. Williamson, Carolyn H Still, Ashley M Couto, Virginia G. Wadley, James J Willard, Alan J. Lerner, Sarah A. Gaussoin, Kaycee M Sink, Laura H. Coker, Bonnie C. Sachs, Gordon J. Chelune, Stephen R. Rapp, and Nicholas M. Pajewski

Subjects
Adult, Male, Ethnic group, Blood Pressure, Neuropsychological Tests, Arts and Humanities (miscellaneous), Developmental and Educational Psychology, Humans, Cognitive Dysfunction, Intervention trial, Aged, Montreal Cognitive Assessment, Regression analysis, Cognition, Middle Aged, Mental Status and Dementia Tests, Regression, Psychiatry and Mental health, Clinical Psychology, Neuropsychology and Physiological Psychology, Blood pressure, Educational Status, Normative, Female, Psychology, Demography
Abstract

To generate robust, demographically-adjusted regression-based norms for the Montreal Cognitive Assessment (MoCA) using a large sample of diverse older US adults. Baseline MoCA scores were examined for participants in the Systolic Blood Pressure Intervention Trial (SPRINT). A robust, cognitively-normal sample was drawn from individuals not subsequently adjudicated with cognitive impairment through 4 years of follow-up. Multivariable Beta-Binomial regression was used to model the association of demographic variables with MoCA performance and to create demographically-stratified normative tables. Participants' (N = 5,338) mean age was 66.9 ± 8.8 years, with 35.7% female, 63.1% White, 27.4% Black, 9.5% Hispanic, and 44.5% with a college or graduate education. A large proportion scored below published MoCA cutoffs: 61.4% scored below 26 and 29.2% scored below 23. A disproportionate number falling below these cutoffs were Black, Hispanic, did not graduate from college, or were ≥75 years of age. Multivariable modeling identified education, race/ethnicity, age, and sex as significant predictors of MoCA scores (p

Published
2021

20. The relationship between depressive symptoms and subtypes of mild cognitive impairment in post‐menopausal women: Results from the Women's Health Initiative Memory Study

Author

Laura E. Korthauer, Joseph S. Goveas, Stephen R. Rapp, Mark A. Espeland, Sally A. Shumaker, Katelyn R. Garcia, Rebecca C. Rossom, Lorena Garcia, Hilary A. Tindle, Elena Salmoirago‐Blotcher, Sylvia Wassertheil‐Smoller, Oleg Zaslavsky, Barbara Cochrane, Kaycee M. Sink, Kamal Masaki, and Ira Driscoll

Subjects
Depression, Neuropsychological Tests, Antidepressive Agents, Hormones, Postmenopause, Psychiatry and Mental health, Risk Factors, Humans, Women's Health, Cognitive Dysfunction, Dementia, Female, Geriatrics and Gerontology, Aged
Abstract

Depressive symptoms are associated with age-related cognitive impairment, but the relative risk of specific subtypes of mild cognitive impairment (MCI) conferred by depressive symptoms is unclear. The purpose of this exploratory study was to determine the longitudinal association between baseline depressive symptoms and incident cases of MCI subtypes (amnestic vs. non-amnestic) and probable dementia (PD) (Alzheimer's disease, vascular, mixed) among postmenopausal women.Depressive symptoms were assessed at study baseline using an 8-item Burnam algorithm in 7043 postmenopausal women who participated in the Women's Health Initiative Memory Study (WHIMS) and the WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) extension study. During the median 9.4-year follow-up interval, the presence of MCI and PD was classified by a central adjudication committee. Classification of participants by MCI subtype (amnestic single and multi-domain, non-amnestic single and multi-domain) was done algorithmically based on established criteria using data from annual cognitive testing.At baseline, 557 women (7.9%) had clinically significant depressive symptoms based on Burnam algorithm cut-point of 0.06. Depressive symptoms at baseline were associated with an increased risk of incident amnestic MCI (hazard ratio [HR] = 1.91, 95% confidence interval [CI] 1.32-2.78, p 0.0001), but not non-amnestic MCI (HR = 1.39, 95% CI 0.91-2.14, p = 0.13) after controlling for demographic factors. This relationship between depressive symptoms and amnestic MCI remained consistent after controlling for lifestyle variables, cardiovascular risk factors, antidepressant use, and history of hormone therapy. There were no significant associations between depressive symptoms and incidence of PD.Depressive symptoms at baseline among postmenopausal older women are associated with higher incidence of amnestic MCI, suggesting that they may be an independent risk factor or part of the early prodrome of dementia.

Published
2022

21. Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials

Author

Susanne Ostrowitzki, Tobias Bittner, Kaycee M. Sink, Howard Mackey, Christina Rabe, Lawrence S. Honig, Emanuele Cassetta, Michael Woodward, Mercè Boada, Christopher H. van Dyck, Timo Grimmer, Dennis J. Selkoe, Andres Schneider, Kathleen Blondeau, Nan Hu, Angelica Quartino, David Clayton, Michael Dolton, Yifan Dang, Beth Ostaszewski, Sandra M. Sanabria-Bohórquez, Michael Rabbia, Balazs Toth, Udo Eichenlaub, Jillian Smith, Lee A. Honigberg, and Rachelle S. Doody

Subjects
Adult, Male, Amyloid beta-Peptides, Treatment Outcome, Double-Blind Method, Alzheimer Disease, Humans, Female, Plaque, Amyloid, Neurology (clinical), Antibodies, Monoclonal, Humanized, Aged
Abstract

ImportanceAlzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression.ObjectiveTo investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD.Design, Setting, and ParticipantsTwo phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively.InterventionsParticipants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks.Main Outcomes and MeasuresThe primary outcome was change from baseline to week 105 in Clinical Dementia Rating–Sum of Boxes (CDR-SB) score.ResultsThere were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was −0.17 (95% CI, −0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point.Conclusions and RelevanceCrenezumab was well tolerated but did not reduce clinical decline in participants with early AD.Trial RegistrationClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657

Published
2022

22. Safety, Tolerability, and Pharmacokinetics of High‐Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers

Author

Amanda Roden, Nan Hu, Logan Brooks, Monica K Wetzel-Smith, Montserrat Carrasco-Triguero, Geoffrey A. Kerchner, Michael J. Dolton, Kathleen Blondeau, Jill Smith, Ariel Waitz, Anita Moein, Kaycee M Sink, Angelica Quartino, Aaron Chesterman, Kun Peng, Ajay Deshmukh, and Susanne Ostrowitzki

Subjects
Adult, Male, Adolescent, Erythema, Hyaluronoglucosaminidase, Antibodies, Monoclonal, Humanized, Infusions, Subcutaneous, Placebo, Infusion Site, Young Adult, Pharmacokinetics, Humans, Medicine, Pharmacology (medical), Adverse effect, Aged, Aged, 80 and over, Pharmacology, business.industry, Middle Aged, Healthy Volunteers, Recombinant Proteins, Bioavailability, Recombinant Human Hyaluronidase, Tolerability, Anesthesia, Drug Therapy, Combination, Female, medicine.symptom, business
Abstract

Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.c. administration (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 and GP40201) that evaluated s.c. crenezumab, an anti-Aβ monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics (PK) in 68 participants (aged 50-80 years) who received single ascending doses (600-7,200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and PK in 72 participants (aged 18-80 years) who received different combinations of dose (1,700-6,800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/minute), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting adverse events in either study. There were no meaningful differences in pain scores among reference placebo (4 mL), test placebo (4-40 mL), or crenezumab (600-7,200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥ 20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but, in some cases, was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately dose-proportional PK, and s.c. bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume s.c. crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile.

Published
2021

23. Effects of intensive versus standard blood pressure control on domain-specific cognitive function: a substudy of the SPRINT randomised controlled trial

Author

Stephen R Rapp, Sarah A Gaussoin, Bonnie C Sachs, Gordon Chelune, Mark A Supiano, Alan J Lerner, Virginia G Wadley, Valarie M Wilson, Lawrence J Fine, Jeff C Whittle, Alexander P Auchus, Srinivasan Beddhu, Dan R Berlowitz, Adam P Bress, Karen C Johnson, Marie Krousel-Wood, Jennifer Martindale-Adams, Eliza C Miller, Dena E Rifkin, Joni K Snyder, Leonardo Tamariz, Dawn F Wolfgram, Maryjo L Cleveland, Mia Yang, Linda O Nichols, Robert Nick Bryan, David M Reboussin, Jeff D Williamson, Nicholas M Pajewski, Alfred K Cheung, Laura H Coker, Michael G Crowe, William C Cushman, Jeffery A Cutler, Christos Davatzikos, Lisa Desiderio, Jimit Doshi, Guray Erus, Darrin Harris, Paul L Kimmel, Manjula K Tamura, Lenore J Launer, Cora E Lewis, Claudia S Moy, Suzanne Oparil, Paula K Ogrocki, Mahboob Rahman, Ilya M Nasrallah, Michael V Rocco, Kaycee M Sink, Carolyn H Still, Jennifer Walker, Daniel E Weiner, Paul K Whelton, Valerie M Wilson, Nancy Woolard, Jackson T Wright, Clinton B Wright, and R Nick Bryan

Subjects
Male, medicine.medical_specialty, Trail Making Test, Blood Pressure, 030204 cardiovascular system & hematology, Verbal learning, law.invention, 03 medical and health sciences, Cognition, 0302 clinical medicine, Randomized controlled trial, law, medicine, Humans, Cognitive Dysfunction, Stroke, Veterans Affairs, Antihypertensive Agents, Aged, Aged, 80 and over, business.industry, Standard treatment, Blood Pressure Monitoring, Ambulatory, Middle Aged, Mental Status and Dementia Tests, medicine.disease, United States, United States Department of Veterans Affairs, Treatment Outcome, Blood pressure, Sprint, Hypertension, Physical therapy, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Summary Background Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. Methods SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov , NCT01206062 . Findings From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7–5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of −0·005 (95% CI −0·010 to 0·001) in the intensive treatment group and −0·001 (–0·006 to 0·005) in the standard treatment group (between-group difference −0·004, 95% CI −0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference −0·010, 95% CI −0·017 to −0·002; p=0·02), with an annual decline of −0·025 (–0·030 to −0·019) for the intensive treatment group and −0·015 (–0·021 to 0·009) for the standard treatment group. Interpretation Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. Funding National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.

Published
2020

24. Baseline demographic, clinical, and cognitive characteristics of the Alzheimer's Prevention Initiative (API) Autosomal‐Dominant Alzheimer's Disease Colombia Trial

Author

Kaycee M Sink, Pierre N. Tariot, Nan Hu, Yakeel T. Quiroz, Michael Malek-Ahmadi, Eric M. Reiman, Yinghua Chen, Howard Mackey, Hillary Protas, Valentina Ghisays, William Cho, Kewei Chen, Heather Guthrie, Yi Su, Dhruman D. Goradia, Claudia Muñoz, Carlos Tobon, Qinshu Lian, Paul S. VanGilder, Ji Luo, Francisco Lopera, Wendy Lee, Paula Ospina, Yamile Bocanegra, Victoria Tirado, Eliana Henao, Silvia Rios-Romenets, Pradeep Thiyyagura, Jillian Smith, Ronald G. Thomas, Jessica B. Langbaum, Margarita Giraldo-Chica, and Natalia Acosta-Baena

Subjects
Adult, Male, medicine.medical_specialty, Epidemiology, preclinical Alzheimer's disease, Disease, Neuropsychological Tests, Placebo, Antibodies, Monoclonal, Humanized, Presenilin, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, autosomal‐dominant Alzheimer's disease, Cognition, Developmental Neuroscience, prevention, Alzheimer Disease, Internal medicine, PSEN1, medicine, preclinical, Presenilin-1, Humans, 030214 geriatrics, baseline data, business.industry, Featured Articles, Health Policy, crenezumab, clinical trial, Genetic Status, Featured Article, Alzheimer's disease, Middle Aged, Clinical trial, Psychiatry and Mental health, Mutation, Alzheimer's Prevention Initiative, Female, Neurology (clinical), Geriatrics and Gerontology, business, Mini-Mental Status Exam, 030217 neurology & neurosurgery
Abstract

Introduction The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo‐controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60‐year‐old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non‐carriers who receive placebo. Methods Of the 252 enrolled, we present data on a total of 242 mutation carriers and non‐carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non‐carriers, 30 to 53 years of age. Carriers were significantly younger than non‐carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non‐carriers. Their demographic characteristics are representative of the local population.

Published
2020

25. Prognostic Awareness, Disease and Palliative Understanding Among Caregivers of Patients With Dementia

Author

Kaycee M Sink, Jeff D. Williamson, Devin Johnson, Jennifer Gabbard, Keren G. Ferris, Shenita Spencer, Laurie E. McLouth, Mia Yang, Greg Russell, and Gretchen A. Brenes

Subjects
Male, Advance care planning, Health Knowledge, Attitudes, Practice, medicine.medical_specialty, Palliative care, Disease, medicine, Humans, Dementia, Intensive care medicine, Aged, Aged, 80 and over, business.industry, Palliative Care, Symptom burden, Cognition, General Medicine, Awareness, Middle Aged, Prognosis, medicine.disease, Cross-Sectional Studies, Caregivers, Socioeconomic Factors, Female, business
Abstract

Background: Persons with dementia (PwD) often have significant cognitive deficits and functional limitations, requiring substantial caregiver assistance. Given the high symptom burden and terminal nature of dementia, good prognostic awareness and integration of palliative care (PC) is needed. Objective: To evaluate prognostic awareness, disease, and PC understanding among caregivers of PwD and to assess for improvements in routine care. Design: A cross-sectional study of 2 cohorts at a single-academic medical center. Surveys were mailed to 200 caregivers of PwD in 2012 (cohort 1). Surveys were sent to new subset of caregivers of PwD (n = 80) in 2018 (cohort 2) to assess trends over time. Results: A total of 154 of caregivers completed the survey (response rate 55%). Compared to 2012, a higher proportion of caregivers in 2018 reported having conversations about prognosis with PwD’s physicians (25% in 2012 vs 45% in 2018; P = .027). However, a large percentage (43% in 2012 and 40% in 2018) of caregivers reported no understanding of the PwD’s prognosis. Despite most stating dementia was not curable, only 39% in 2012 and 52% in 2018 ( P = .015) understood that dementia was a terminal disease. In addition, only 32% in 2012 and 40% in 2018 ( P = .39) felt that they were knowledgeable about PC. Conclusions: Prognostic discussions between caregivers of PwD and the PwD’s physicians may be occurring more often; however, a high percentage of caregivers report a poor understanding about the terminal nature of dementia and the role of PC.

Published
2019

26. Strategies for activity maintenance in patient and family care and clinical trial adherence of GNA social plan in context of COVID‐19 health emergency

Author

Angela M Andrade‐Villegas, David Aguillon, Manuela Gómez, Clara Gómez‐Henck, Maria Zuluaga, Sofia Rassi, Claudia Ramos, Claudia Madrigal, Claramonika Uribe, Amanda Saldarriaga, Diana Alzate, Alejandra Ruiz, Andrea Giraldo, Margarita Giraldo‐Chica, Eric M Reiman, Kaycee M Sink, Silvia Rios‐Romenets, Lucia Madrigal, and Francisco Lopera

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021

27. Mild cognitive impairment and transitions in cognitive status in the Systolic Blood Pressure Intervention Trial (SPRINT)

Author

Sarah A Gaussoin, Nicholas M Pajewski, Gordon Chelune, Maryjo Cleveland, Michael G Crowe, Lenore J Launer, Alan J Lerner, Jennifer Martindale‐Adams, Linda O Nichols, Paula K Ogrocki, Bonnie C Sachs, Kaycee M Sink, Mark A Supiano, Virginia G Wadley, Valerie M Wilson, Clinton B Wright, Jeff D Williamson, David M Reboussin, and Stephen R Rapp

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021

28. Psychological status in the participants of the API ADAD Colombia trial assisted by a comprehensive mental health program during COVID 19 pandemic

Author

Claudia Ramos, Claudia Madrigal, Margarita Giraldo‐Chica, Natalia Acosta‐Baena, Claudia Aponte, David Aguillon, Manuela Gómez, Alejandro Espinosa, Lucia Madrigal, Claramonika Uribe, Amanda Saldarriaga, Diana Alzate, Alejandra Ruiz, Angela M Andrade‐Villegas, Hugo Elias Lopez, Jessica B Langbaum, Kaycee M Sink, Eric M Reiman, Pierre N Tariot, Silvia Rios‐Romenets, and Francisco Lopera

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021

29. Effect of Intensive Blood Pressure Control on Subtypes of Mild Cognitive Impairment and Risk of Progression from SPRINT study

Author

Michael Crowe, Virginia G. Wadley, Paula Ogrocki, Valerie M. Wilson, Sarah A. Gaussoin, Mark A. Supiano, Nicholas M. Pajewski, Clinton B. Wright, David M. Reboussin, Bonnie C. Sachs, Stephen R. Rapp, Lenore J. Launer, Alan J. Lerner, Gordon J. Chelune, Jennifer Martindale-Adams, Kaycee M Sink, Linda O. Nichols, Jeff D. Williamson, and Maryjo Cleveland

Subjects
medicine.medical_specialty, Blood Pressure, Neuropsychological Tests, Article, law.invention, Randomized controlled trial, law, Internal medicine, mental disorders, Medicine, Dementia, Humans, Cognitive Dysfunction, Survival analysis, Aged, Proportional Hazards Models, business.industry, Standard treatment, Hazard ratio, medicine.disease, Confidence interval, Clinical trial, Blood pressure, Hypertension, Disease Progression, Female, Geriatrics and Gerontology, business
Abstract

BACKGROUND: To examine the effect of intensive blood pressure control on the occurrence of subtypes of mild cognitive impairment (MCI) and determine the risk of progression to dementia or death. METHODS: Secondary analysis of a randomized trial of community-dwelling adults (≥50 years) with hypertension. Participants were randomized to a systolic blood pressure (SBP) goal of

Published
2021

30. Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure

Author

Manjula Kurella Tamura, Sarah Gaussoin, Nicholas M. Pajewski, Greg Zaharchuk, Barry I. Freedman, Stephen R. Rapp, Alexander P. Auchus, William E. Haley, Suzanne Oparil, Jessica Kendrick, Christianne L. Roumie, Srinivasan Beddhu, Alfred K. Cheung, Jeff D. Williamson, John A. Detre, Sudipto Dolui, R. Nick Bryan, Ilya M. Nasrallah, Paul Whelton, Karen C. Johnson, Joni Snyder, Diane Bild, Denise Bonds, Nakela Cook, Jeffrey Cutler, Lawrence Fine, Peter Kaufmann, Paul Kimmel, Lenore Launer, Claudia Moy, William Riley, Laurie Ryan, Eser Tolunay, Song Yang, David Reboussin, Jeff Williamson, Walter T. Ambrosius, William Applegate, Greg Evans, Capri Foy, Dalane Kitzman, Mary Lyles, Nick Pajewski, Steve Rapp, Scott Rushing, Neel Shah, Kaycee M. Sink, Mara Vitolins, Lynne Wagenknecht, Valerie Wilson, Letitia Perdue, Nancy Woolard, Tim Craven, Katelyn Garcia, Laura Lovato, Jill Newman, James Lovato, Lingyi Lu, Chris McLouth, Greg Russell, Bobby Amoroso, Patty Davis, Jason Griffin, Darrin Harris, Mark King, Kathy Lane, Wes Roberson, Debbie Steinberg, Donna Ashford, Phyllis Babcock, Dana Chamberlain, Vickie Christensen, Loretta Cloud, Christy Collins, Delilah Cook, Katherine Currie, Debbie Felton, Stacy Harpe, Marjorie Howard, Michelle Lewis, Pamela Nance, Nicole Puccinelli-Ortega, Laurie Russell, Jennifer Walker, Brenda Craven, Candace Goode, Margie Troxler, Janet Davis, Sarah Hutchens, Anthony A. Killeen, Anna M. Lukkari, Robert Ringer, Brandi Dillard, Norbert Archibeque, Stuart Warren, Mike Sather, James Pontzer, Zach Taylor, Elsayed Z. Soliman, Zhu-Ming Zhang, Yabing Li, Chuck Campbell, Susan Hensley, Julie Hu, Lisa Keasler, Mary Barr, Tonya Taylor, Christos Davatzikos, Ilya Nasarallah, Lisa Desiderio, Mark Elliott, Ari Borthakur, Harsha Battapady, Guray Erus, Alex Smith, Ze Wang, Jimit Doshi, Jackson T. Wright, Mahboob Rahman, Alan J. Lerner, Carolyn Still, Alan Wiggers, Sara Zamanian, Alberta Bee, Renee Dancie, George Thomas, Martin Schreiber, Sankar Dass Navaneethan, John Hickner, Michael Lioudis, Michelle Lard, Susan Marczewski, Jennifer Maraschky, Martha Colman, Andrea Aaby, Stacey Payne, Melanie Ramos, Carol Horner, Paul Drawz, Pratibha P. Raghavendra, Scott Ober, Ronda Mourad, Muralidhar Pallaki, Peter Russo, Pratibha Raghavendra, Pual Fantauzzo, Lisa Tucker, Bill Schwing, John R. Sedor, Edward J. Horwitz, Jeffrey R. Schellling, John F. O’Toole, Lisa Humbert, Wendy Tutolo, Suzanne White, Alishea Gay, Walter Clark, Robin Hughes, Mirela Dobre, Carolyn H. Still, Monique Williams, Udayan Bhatt, Lee Hebert, Anil Agarwal, Melissa Brown Murphy, Nicole Ford, Cynthia Stratton, Jody Baxter, Alicia A. Lykins, Alison McKinley Neal Leena Hirmath, Osei Kwame, Kyaw Soe, William F. Miser, Colleen Sagrilla, Jan Johnston, Amber Anaya, Ashley Mintos, Angel A. Howell, Kelly Rogers, Sara Taylor, Donald Ebersbacher, Lucy Long, Beth Bednarchik, Adrian Schnall, Jonathan Smith, Lori Peysha, Lisa Leach, Megan Tribout, Carla Harwell, Pinkie Ellington, Mary Ann Banerji, Pranav Ghody, Melissa Vahídeh Rambaud, Raymond Townsend, Debbie Cohen, Yonghong Huan, Mark Duckworth, Virginia Ford, Juliet Leshner, Ann Davison, Sarah Vander Veen, Crystal A. Gadegbeku, Avi Gillespie, Anuradha Paranjape, Sandra Amoroso, Zoe Pfeffer, Sally B. Quinn, Jiang He, Jing Chen, Eva Lustigova, Erin Malone, Marie Krousel-Wood, Richard Deichmann, Patricia Ronney, Susan Muery, Donnalee Trapani, Michael Rocco, David Goff, Carlos Rodriguez, Laura Coker, Amret Hawfield, Joseph Yeboah, Lenore Crago, John Summerson, Anita Hege, Matt Diamond, Laura Mulloy, Marcela Hodges, Michelle Collins, Charlene Weathers, Heather Anderson, Emily Stone, Walida Walker, Andrew McWilliams, Michael Dulin, Lindsay Kuhn, Susan Standridge, Lindsay Lowe, Kelly Everett, Kelry Preston, Susan Norton, Silena Gaines, Ali A. Rizvi, Andrew W. Sides, Diamond Herbert, Matthew M. Hix, Melanie Whitmire, Brittany Arnold, Philip Hutchinson, Joseph Espiritu, Mark Feinglos, Eugene Kovalik, Georgianne Gedon-Lipscomb, Kathryn Evans, Connie Thacker, Ronna Zimmer, Mary Furst, MaryAnn Mason, James Powell, Paul Bolin, Junhong Zhang, Mary Pinion, Gail Davis, Winifred Bryant, Presley Phelps, Connie Garris-Sutton, Beatrice Atkinson, Gabriele Contreras, Maritza Suarez, Ivonne Schulman, Don Koggan, Jackie Vassallo, Gloria Peruyera, Sheri Whittington, Cassandra Bethea, Laura Gilliam, Carolyn Pedley, Geraldine Zurek, Miriam Baird, Charles Herring, Mary Martha Smoak, Julie Williams, Samantha Rogers, Lindsay Gordon, Erin Kennedy, Beverly Belle, Jessica McCorkle-Doomy, Jonathan Adams, Ramon Lopez, Juris Janavs, Frederic Rahbari-Oskoui, Arlene Chapman, Allen Dollar, Olubunmi Williams, Yoosun Han, William Haley, Peter Fitzpatrick, Joseph Blackshear, Brian Shapiro, Anna Harrell, Arta Palaj, Katelyn Henderson, Ashley Johnson, Heath Gonzalez, Jermaine Robinson, Leonardo Tamariz, Jennifer Denizard, Rody Barakat, Dhurga Krishnamoorthy, Frank Greenway, Ron Monce, Timothy Church, Chelsea Hendrick, Aimee Yoches, Leighanne Sones, Markee Baltazar, Priscilla Pemu, Connie Jones, Derrick Akpalu, Gordon Chelune, Jeffrey Childs, Lisa Gren, Anne Randall, Laura Dember, Denise Soares, Jerry Yee, Kausik Umanath, Naima Ogletree, Schawana Thaxton, Karen Campana, Dayna Sheldon, Krista MacArthur, J. Brent Muhlestein, Nathan Allred, Brian Clements, Ritesh Dhar, Kent Meredith, Viet Le, Edward Miner, James Orford, Erik R. Riessen, Becca Ballantyne, Ben Chisum, Kevin Johnson, Dixie Peeler, Glenn Chertow, Manju Tamura, Tara Chang, Kevin Erickson, Jenny Shen, Randall S. Stafford, Gregory Zaharchuk, Margareth Del Cid, Michelle Dentinger, Jennifer Sabino, Rukmani Sahay, Ekaterina Telminova, Daniel E. Weiner, Mark Sarnak, Lily Chan, Amanda Civiletto, Alyson Heath, Amy Kantor, Priyanka Jain, Bethany Kirkpatrick, Andrew Well, Barry Yuen, Michel Chonchol, Beverly Farmer, Heather Farmer, Carol Greenwald, Mikaela Malaczewski, James Lash, Anna Porter, Ana Ricardo, Robert T. Rosman, Janet Cohan, Nieves Lopez Barrera, Daniel Meslar, Patricia Meslar, Margaret Conroy, Mark Unruh, Rachel Hess, Manisha Jhamb, Holly Thomas, Pam Fazio, Elle Klixbull, Melissa Komlos-Weimer, LeeAnne Mandich, Tina Vita, Robert Toto, Peter Van Buren, Julia Inrig, Martha Cruz, Tammy Lightfoot, Nancy Wang, Lori Webster, Kalani Raphael, Barry Stults, Tahir Zaman, Debra Simmons, Tooran Lavasani, Rebecca Filipowicz, Guo Wei, Gracie Mary Miller, Jenice Harerra, Jeff Christensen, Ajay Giri, Xiaorui Chen, Natalie Anderton, Arianna Jensen, Julia Lewis, Anna Burgner, Jamie P. Dwyer, Gerald Schulman, Terri Herrud, Ewanda Leavell, Tiffany McCray, Edwina McNeil-Simaan, Munmun Poudel, Malia Reed, Mohammed Sika, Delia Woods, Janice L. Zirkenbach, Dominic S. Raj, Scott Cohen, Samir Patel, Manuel Velasquez, Roshni S. Bastian, Maria Wing, Akshay Roy-Chaudhury, Thomas Depner, Lorien Dalyrymple, George Kaysen, Susan Anderson, John Nord, Joachim H. Ix, Leonard Goldenstein, Cynthia M. Miracle, Nketi Forbang, Maja Mircic, Brenda Thomas, Tiffany Tran, Anjay Rastogi, Mihae Kim, Mohamad Rashid, Bianca Lizarraga, Amy Hocza, Kristine Sarmosyan, Jason Norris, Tushar Sharma, Amanda Chioy, Eric Bernard, Eleanore Cabrera, Christina Lopez, Susana Nunez, Joseph Riad, Suzanne Schweitzer, Siran Sirop, Sarah Thomas, Lauren Wada, Holly Kramer, Vinod Bansal, Corliss E. Taylor, Mark S. Segal, Karen L. Hall, Amir Kazory, Lesa Gilbert, Linda Owens, Danielle Poulton, Elaine Whidden, Jocelyn Wiggins, Caroline Blaum, Linda Nyquist, Lillian Min, Tanya Gure, Ruth Lewis, Jennifer Mawby, Eileen Robinson, Cora E. Lewis, Virginia Bradley, David Calhoun, Stephen Glasser, Kim Jenkins, Tom Ramsey, Nauman Qureshi, Karen Ferguson, Sumrah Haider, Mandy James, Christy Jones, Kim Renfroe, April Seay, Carrie Weigart, Denyse Thornley-Brown, Dana Rizik, Bari Cotton, Meredith Fitz-Gerald, Tiffany Grimes, Carolyn Johnson, Sara Kennedy, Chanel Mason, Lesa Rosato-Burson, Robin Willingham, Eric Judd, Tonya Breaux-Shropshire, Felice Cook, Julia Medina, Lama Ghazi, Hemal Bhatt, James Lewis, Roman Brantley, John Brouilette, Jeffrey Glaze, Stephanie Hall, Nancy Hiott, David Tharpe, Spencer Boddy, Catherine Mack, Catherine Womack, Keiko Asao, Beate Griffin, Carol Hendrix, Karen Johnson, Lisa Jones, Chelsea Towers, Henry Punzi, Kathy Cassidy, Kristin Schumacher, Carmen Irizarry, Ilma Colon, Pedro Colon-Ortiz, Pedro J. Colón-Hernández, Orlando J. Carrasquillo-Navarro, Merari Carrasquillo, Nivea Vazquez, Miguel Sosa-Padilla, Alex Cintron-Pinero, Mayra Ayala, Olga Pacheco, Catalina Rivera, Irma Sotomayor-Gonzalez, Jamie Claudio, Jose Lazaro, Migdalia Arce, Lourdes Heres, Alba Perez, Jose Tavarez-Valle, Ferlinda Arocho, Mercedes Torres, Melvaliz Vazquez, Gerard P. Aurigemma, Rebecca Takis-Smith, Julia Andrieni, Noelle Bodkin, Kiran Chaudhary, Paula Hu, John Kostis, Nora Cosgrove, Denise Bankowski, Monica Boleyn, Laurie Casazza, Victoria Giresi, Tosha Patel, Erin Squindo, Yan Wu, Zeb Henson, Marion Wofford, Jessica Lowery, Deborah Minor, Kimberley Harkins, Alexander Auchus, Michael Flessner, Cathy Adair, Jordan Asher, Debbie Loope, Rita Cobb, Reiner Venegas, Thomas Bigger, Natalie Bello, Shunichi Homma, Daniel Donovan, Carlos Lopez-Jimenez, Amilcar Tirado, Asqual Getaneh, Rocky Tang, Sabrina Durant, Mathew Maurer, Sergio Teruya, Stephen Helmke, Julissa Alvarez, Ruth Campbell, Roberto Pisoni, Rachel Sturdivant, Deborah Brooks, Caroline Counts, Vickie Hunt, Lori Spillers, Donald Brautigam, Timothy Kitchen, Timothy Gorman, Jessica Sayers, Sarah Button, June Chiarot, Rosemary Fischer, Melissa Lyon, Maria Resnick, Nicole Hodges, Jennifer Ferreira, William Cushman, Barry Wall, Linda Nichols, Robert Burns, Jennifer Martindale-Adams, Dan Berlowitz, Elizabeth Clark, Sandy Walsh, Terry Geraci, Carol Huff, Linda Shaw, Karen Servilla, Darlene Vigil, Terry Barrett, Mary Ellen Sweeney, Rebecca Johnson, Susan McConnell, Khadijeh Shahid Salles, Francoise Watson, Cheryl Schenk, Laura Whittington, Maxine Maher, Jonathan Williams, Stephen Swartz, Paul Conlin, George Alexis, Rebecca Lamkin, Patti Underwood, Helen Gomes, Clive Rosendorff, Stephen Atlas, Saadat Khan, Waddy Gonzalez, Samih Barcham, Lawrence Kwon, Matar Matar, Anwar Adhami, Jan Basile, Joseph John, Deborah Ham, Hadi Baig, Mohammed Saklayen, Jason Yap, Helen Neff, Carol Miller, Ling Zheng-Phelan, Saib Gappy, Shiva Rau, Arathi Raman, Vicki Berchou, Elizabeth Jones, Erin Olgren, Cynthia Marbury, Michael Yudd, Sithiporn Sastrasinh, Jennine Michaud, Jessica Fiore, Marianne Kutza, Ronald Shorr, Rattana Mount, Helen Dunn, Susan Stinson, Jessica Hunter, Addison Taylor, Jeffery Bates, Catherine Anderson, Kent Kirchner, Jodi Stubbs, Ardell Hinton, Anita Spencer, Santosh Sharma, Thomas Wiegmann, Smita Mehta, Michelle Krause, Kate Dishongh, Richard Childress, Geeta Gyamlani, Atossa Niakan, Cathy Thompson, Janelle Moody, Carolyn Gresham, Jeffrey Whittle, Gary Barnas, Dawn Wolfgram, Heidi Cortese, Jonette Johnson, Christianne Roumie, Adriana Hung, Jennifer Wharton, Kurt Niesner, Lois Katz, Elizabeth Richardson, George Brock, Joanne Holland, Troy Dixon, Athena Zias, Christine Spiller, Penelope Baker, James Felicetta, Shakaib Rehman, Kelli Bingham, Suzanne Watnick, David Cohen, Jessica Weiss, Tera Johnston, Stephen Giddings, Hala Yamout, Andrew Klein, Caroline Rowe, Kristin Vargo, Kristi Waidmann, Vasilios Papademetriou, Jean Pierre Elkhoury, Barbara Gregory, Susan Amodeo, Mary Bloom, Dalia Goldfarb-Waysman, Richard Treger, Mehran Kashefi, Christina Huang, Karen Knibloe, Areef Ishani, Yelena Slinin, Christine Olney, Jacqueline Rust, Paolo Fanti, Christopher Dyer, Shweta Bansal, Monica Dunnam, Lih-Lan Hu, and Perla Zarate-Abbott

Subjects
Male, medicine.medical_specialty, Renal function, Perfusion scanning, Blood Pressure, Article, chemistry.chemical_compound, Internal medicine, medicine, Humans, Cerebral perfusion pressure, Renal Insufficiency, Chronic, Antihypertensive Agents, Aged, Creatinine, business.industry, medicine.disease, Perfusion, Blood pressure, chemistry, Cerebral blood flow, Nephrology, Cerebrovascular Circulation, Hypertension, Albuminuria, Cardiology, Female, medicine.symptom, business, Kidney disease, Glomerular Filtration Rate
Abstract

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

Published
2021

31. The Association between the Montreal Cognitive Assessment and Functional Activity Questionnaire in the Systolic Blood Pressure Intervention Trial (SPRINT)

Author

Alan J. Lerner, Gordon J. Chelune, Virginia G. Wadley, Kaycee M Sink, Nicholas M. Pajewski, Stephen R. Rapp, Carolyn H Still, and Jeff D. Williamson

Subjects
Male, 050103 clinical psychology, Percentile, medicine.medical_specialty, Activities of daily living, Odds, Cardiovascular disease, Assessment, Clinical trials, Activities of Daily Living, medicine, Dementia, Humans, 0501 psychology and cognitive sciences, Cognitive Dysfunction, Aged, Randomized Controlled Trials as Topic, business.industry, 05 social sciences, Montreal Cognitive Assessment, Mild cognitive impairment, Cognition, General Medicine, Middle Aged, medicine.disease, Mental Status and Dementia Tests, Health Surveys, Psychiatry and Mental health, Clinical Psychology, Neuropsychology and Physiological Psychology, Blood pressure, Cross-Sectional Studies, Sprint, Hypertension, Physical therapy, Female, Original Empirical Article, business, human activities
Abstract

Objective To examine the association of global cognitive function assessed via the Montreal Cognitive Assessment (MoCA) and deficiencies in instrumental activities of daily living (IADL) on the Functional Activity Questionnaire (FAQ) in hypertensive older adults in the Systolic Blood Pressure Intervention Trial (SPRINT). Methods In cross-sectional analysis, 9,296 SPRINT participants completed the MoCA at baseline. The FAQ was obtained from 2,705 informants for SPRINT participants scoring Results Participants who triggered FAQ administration were older, less educated, and more likely to be Black or Hispanic (p < 0.001). Sixty-one percent (n = 1,661) of participants’ informants reported no functional difficulties in IADLs. An informant report, however, of any difficulty on the FAQ was associated with lower MoCA scores after controlling for age, sex, race/ethnicity, and education (p < 0.05). Partial proportional odds regression indicates that participants scoring lower on the MoCA (in the 10th to Conclusions While lower global cognitive function was strongly associated with IADL deficits on FAQ, informants indicated no functional difficulties for the majority of SPRINT participants, despite low MoCA scores. These findings can help with designing future studies which aim to detect mild cognitive impairment and/or dementia in large, community-dwelling populations.

Published
2018

32. Final Report of a Trial of Intensive versus Standard Blood-Pressure Control

Author

David M. Reboussin, Jeffrey A. Cutler, Srinivasan Beddhu, William C. Cushman, Joni K. Snyder, Jeff D. Williamson, Paul K. Whelton, Walter T. Ambrosius, Karen C. Johnson, Jackson T. Wright, Suzanne Oparil, Cora E. Lewis, Alfred K. Cheung, Dalane W. Kitzman, Lawrence J. Fine, Gregory W. Evans, Kaycee M. Sink, Michael V. Rocco, and Mahboob Rahman

Subjects
Male, medicine.medical_specialty, Acute decompensated heart failure, Blood Pressure, 030204 cardiovascular system & hematology, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Stroke, Antihypertensive Agents, Aged, business.industry, Standard treatment, Hazard ratio, General Medicine, Middle Aged, medicine.disease, Blood pressure, Cardiovascular Diseases, Heart failure, Hypertension, Cardiology, Female, business, Follow-Up Studies
Abstract

BACKGROUND: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected. METHODS: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure

Published
2021

33. Sex differences in neurodegeneration and memory performance in preclinical autosomal dominant Alzheimer’s disease: Baseline findings from the API ADAD trial

Author

Carlos Tobon, Yamile Bocanegra, Michael Malek-Ahmadi, Dhruman D. Goradia, Wendy Lee, Valentina Ghisays, Hillary Protas, Jessica B. Langbaum, Margarita Giraldo-Chica, Ronald G. Thomas, Natalia Acosta-Baena, Paula Ospina, Victoria Tirado, Ji Luo, Nan Hu, Yakeel T. Quiroz, Yinghua Chen, Yi Su, David Clayton, Claudia Muñoz, Eric M. Reiman, Kaycee M Sink, Ernesto Luna-Maldonado, Pierre N. Tariot, Sergio Alvarez, Marisol Londono, Clara Vila-Castelar, Silvia Rios-Romenets, Eliana Henao, and Francisco Lopera

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Neurodegeneration, Disease, Memory performance, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, Baseline (configuration management), business
Published
2020

34. Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks

Author

Susanne Ostrowitzki, Jillian Smith, Angelica Quartino, Michael J. Dolton, Lawrence S. Honig, Montserrat Carrasco-Triguero, Tobias Bittner, Heather Guthrie, Helen Lin, David Clayton, Kathleen Blondeau, Qinshu Lian, and Kaycee M Sink

Subjects
0301 basic medicine, Male, Hemosiderosis, Gastroenterology, 0302 clinical medicine, Medicine, magnetic resonance imaging, Aged, 80 and over, education.field_of_study, General Neuroscience, Brain, General Medicine, Middle Aged, Psychiatry and Mental health, Clinical Psychology, Treatment Outcome, Tolerability, Effusion, Cohort, humanized monoclonal antibody, Female, Alzheimer’s disease, Research Article, safety, medicine.medical_specialty, Population, Neuroimaging, Placebo, Antibodies, Monoclonal, Humanized, amyloid-β peptide, 03 medical and health sciences, Pharmacokinetics, Double-Blind Method, Alzheimer Disease, Internal medicine, Humans, education, Adverse effect, Aged, infusion site adverse event, Amyloid beta-Peptides, amyloid positron emission tomography, business.industry, crenezumab, medicine.disease, 030104 developmental biology, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Background Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level. Conclusion Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

Published
2020

35. Computer simulations for assessing cognitively intensive instrumental activities of daily living in older adults

Author

Edward H. Ip, Valerie Wilson, Dana Chamberlain, Lingyi Lu, Stephen R. Rapp, Kaycee M. Sink, and Ryan T. Barnard

Subjects
medicine.medical_specialty, Activities of daily living, lcsh:Geriatrics, Audiology, Assessment, lcsh:RC346-429, 03 medical and health sciences, Computer, 0302 clinical medicine, Functional abilities, Validation, medicine, Dementia, 030212 general & internal medicine, Cognitive impairment, lcsh:Neurology. Diseases of the nervous system, Reliability (statistics), Face validity, Receiver operating characteristic, Cognition, medicine.disease, lcsh:RC952-954.6, Psychiatry and Mental health, Cognitive & Behavioral Assessment, Neurology (clinical), Psychology, 030217 neurology & neurosurgery, Simulation
Abstract

Introduction Aim is to evaluate validity, reliability, diagnostic precision, and user acceptability of computer simulations of cognitively demanding tasks when administered to older adults with and without cognitive impairment. Methods Five simulation modules were administered to 161 individuals aged ≥60 years with no cognitive impairment (N = 81), mild cognitive impairment (N = 52), or dementia (N = 28). Groups were compared on total accuracy and time to complete the tasks (seconds). Receiver operating characteristics were evaluated. Reliability was assessed over one month. Participants rated face validity and acceptability. Results Total accuracy (P

Published
2018

36. Associations of Early Kidney Disease With Brain Magnetic Resonance Imaging and Cognitive Function in African Americans With Type 2 Diabetes Mellitus

Author

Jeff D. Williamson, R. Nick Bryan, Lenore J. Launer, Joshua I. Barzilay, S. Carrie Smith, Jianzhao Xu, Timothy M. Hughes, Mark Sullivan, Christina E. Hugenschmidt, Nicholette D. Palmer, Donald W. Bowden, Christopher T. Whitlow, Michael E. Miller, Jasmin Divers, Benjamin C. Wagner, Barry I. Freedman, Robert M. Cohen, Laura C. Lovato, Joseph A. Maldjian, and Kaycee M. Sink

Subjects
Male, 030232 urology & nephrology, Neuropsychological Tests, Cognition, 0302 clinical medicine, Gray Matter, medicine.diagnostic_test, Smoking, Brain, Organ Size, Middle Aged, Magnetic Resonance Imaging, White Matter, Cardiovascular Diseases, Nephrology, Creatinine, Hypertension, Cardiology, Female, medicine.symptom, Glomerular Filtration Rate, medicine.medical_specialty, Renal function, Article, 03 medical and health sciences, Internal medicine, Diabetes mellitus, medicine, Albuminuria, Humans, Cognitive Dysfunction, Renal Insufficiency, Chronic, Aged, Glycated Hemoglobin, business.industry, Type 2 Diabetes Mellitus, Magnetic resonance imaging, Cholesterol, LDL, medicine.disease, United States, Black or African American, Cross-Sectional Studies, Endocrinology, Diabetes Mellitus, Type 2, Multivariate Analysis, Linear Models, business, Neurocognitive, Body mass index, 030217 neurology & neurosurgery, Kidney disease
Abstract

Background Relationships between early kidney disease, neurocognitive function, and brain anatomy are poorly defined in African Americans with type 2 diabetes mellitus (T2DM). Study Design Cross-sectional associations were assessed between cerebral anatomy and cognitive performance with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in African Americans with T2DM. Setting & Participants African Americans with cognitive testing and cerebral magnetic resonance imaging (MRI) in the African American−Diabetes Heart Study Memory in Diabetes (AA-DHS MIND; n=512; 480 with MRI) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) MIND (n=484; 104 with MRI) studies. Predictors eGFR (CKD-EPI creatinine equation), spot UACR. Measurements MRI-based cerebral white matter volume (WMV), gray matter volume (GMV), and white matter lesion volume; cognitive performance (Mini-Mental State Examination, Digit Symbol Coding, Stroop Test, and Rey Auditory Verbal Learning Test). Multivariable models adjusted for age, sex, body mass index, scanner, intracranial volume, education, diabetes duration, hemoglobin A1c concentration, low-density lipoprotein cholesterol concentration, smoking, hypertension, and cardiovascular disease were used to test for associations between kidney phenotypes and the brain in each study; a meta-analysis was performed. Results Mean participant age was 60.1±7.9 (SD) years; diabetes duration, 12.1±7.7 years; hemoglobin A1c concentration, 8.3%±1.7%; eGFR, 88.7±21.6mL/min/1.73m2; and UACR, 119.2±336.4mg/g. In the fully adjusted meta-analysis, higher GMV associated with lower UACR (P Limitations Cross-sectional; single UACR measurement. Conclusions In African Americans with T2DM, mildly high UACR and mildly low eGFR were associated with smaller GMV and increased white matter lesion volume. UACR was associated with poorer processing speed and working memory.

Published
2017

37. Negative Affect Is Associated With Higher Risk of Incident Cognitive Impairment in Nondepressed Postmenopausal Women

Author

Mark A. Espeland, Katelyn R. Garcia, Joseph S. Goveas, Hilary A. Tindle, Laura E. Korthauer, Susan M. Resnick, Elena Salmoirago-Blotcher, Stephen R. Rapp, Kaycee M. Sink, Sally A. Shumaker, Leslie Vaughan, and Ira Driscoll

Subjects
Aging, medicine.medical_treatment, Affect (psychology), 050105 experimental psychology, Developmental psychology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Humans, Dementia, Cognitive Dysfunction, 0501 psychology and cognitive sciences, Longitudinal Studies, Cognitive decline, Risk factor, Depression (differential diagnoses), Aged, Aged, 80 and over, Depressive Disorder, business.industry, Incidence, 05 social sciences, Cognition, medicine.disease, United States, Postmenopause, Affect, The Journal of Gerontology: Medical Sciences, Anxiety, Female, Hormone therapy, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Background Positive affect (PA) and negative affect (NA) reflect subjective emotional experiences. Although related to depression and anxiety, these dimensions are distinct constructs representing affective states and patterns. Prior studies suggest that elevated depressive symptoms are associated with risk of mild cognitive impairment (MCI) and probable dementia, but whether affective states are associated with cognitive impairment is still unknown. The present study examined relationships between baseline affective states and cognitive impairment (MCI, probable dementia) in nondepressed women. Method Baseline PA and NA were assessed in postmenopausal women (N = 2,137; mean age = 73.8 years) from the Women's Health Initiative Study of Cognitive Aging (WHISCA) using the Positive and Negative Affect Schedule (PANAS). Women were followed annually for an average of 11.3 years; those with elevated depressive symptoms at baseline were excluded. Results Higher NA was associated with a higher risk of MCI and probable dementia, even after adjusting for important covariates including age, education, sociodemographic, lifestyle, and cardiovascular risk factors, global cognition, and hormone therapy assignment at baseline. PA was not significantly associated with either outcome. Conclusions We present the first evidence to date that greater NA, even in the absence of elevated depressive symptoms, is associated with higher risk of MCI and dementia. This suggests that NA may be an important, measureable and potentially modifiable risk factor for age-related cognitive decline.

Published
2017

38. 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

39. Effects of Intensive BP Control in CKD

Author

Paul L. Kimmel, Lois A. Katz, Jerry Yee, William E. Haley, Anthony A. Killeen, Barry I. Freedman, Ana C. Ricardo, Tom Greene, Barry M. Wall, Tara I. Chang, Timothy E. Craven, Alfred K. Cheung, Karen S. Servilla, Dawn F. Wolfgram, Karen C. Johnson, Jan Basile, Cora E. Lewis, Amret T. Hawfield, William C. Cushman, Glenn M. Chertow, Mahboob Rahman, Srinivasan Beddhu, Kaycee M. Sink, Michel Chonchol, David M. Reboussin, Udayan Bhatt, Paul K. Whelton, Jackson T. Wright, Suzanne Oparil, Vasilios Papademetriou, Joachim H. Ix, and Michael V. Rocco

Subjects
medicine.medical_specialty, Acute coronary syndrome, business.industry, Hazard ratio, 030232 urology & nephrology, Renal function, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, Confidence interval, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Nephrology, Internal medicine, Diabetes mellitus, medicine, Adverse effect, business, Cause of death
Abstract

The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of

Published
2017

40. The Feasibility of Walnut and Extra Virgin Olive Oil Supplementation in Older Adults

Author

David M. Reboussin, Ommega Internationals, Caroline S. Blackwell, Jeff D. Williamson, Lindsay M. Reynolds, Robert P. Byington, Mara Z. Vitolins, Sharon Wilmoth, Capri G. Foy, and Kaycee M. Sink

Subjects
business.industry, General Earth and Planetary Sciences, Medicine, Food science, business, General Environmental Science, Olive oil
Published
2017

41. Integrating Frailty Research into the Medical Specialties-Report from a U13 Conference

Author

Brian Buta, Susan J. Zieman, Melissa K. Andrew, Patrick J. Brown, Thomas N. Robinson, E. Wesley Ely, Ravi Varadhan, Arti Hurria, Chris Carpenter, Felipe Sierra, Kaycee M. Sink, Luigi Ferrucci, Jeremy D. Walston, Stephen B. Kritchevsky, Kenneth E. Schmader, Kenneth Rockwood, Frances McFarland, Keri N. Althoff, Caroline Blaum, and Kevin P. High

Subjects
Gerontology, Research program, medicine.medical_specialty, Biomedical Research, Frail Elderly, Human immunodeficiency virus (HIV), Specialty, Vulnerability, 030204 cardiovascular system & hematology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, 030212 general & internal medicine, Geriatric Assessment, Aged, Aged, 80 and over, Geriatrics, business.industry, Stressor, Congresses as Topic, 3. Good health, Frailty assessment, Research questions, Geriatrics and Gerontology, business
Abstract

Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as increased vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, HIV care, nephrology, and in the behavioral and social sciences. Incorporation of frailty assessment and frailty research into the specialties is hindered by a lack of a consensus definition, by the proliferation of measurement tools, inadequate understanding of the biology of frailty, and lack of validated clinical algorithms for patients who have frailty. In 2015, the American Geriatrics Society, the National Institute on Aging (NIA) and the Alliance for Academic Internal Medicine held a conference for awardees of the NIA sponsored ‘Grants for Early Medical/Surgical Specialists Transition into Aging Research (GEMSSTAR)’1 program to review the current state of the knowledge regarding frailty in the sub-specialties, as well as to highlight key examples of integrating frailty research into the medical specialties. Key research questions to advance frailty research into specialty medicine are proposed.

Published
2017

42. Dynapenia and Metabolic Health in Obese and Nonobese Adults Aged 70 Years and Older: The LIFE Study

Author

Mylène Aubertin-Leheudre, Stephen Anton, Daniel P. Beavers, Todd M. Manini, Roger Fielding, Ann Newman, Tim Church, Stephen B. Kritchevsky, David Conroy, Mary M. McDermott, Anda Botoseneanu, Michelle E. Hauser, Marco Pahor, Thomas Gill, Carlos Fragoso, Jack M. Guralnik, Christiaan Leeuwenburgh, Connie Caudle, Lauren Crump, Latonia Holmes, Jocelyn Lee, Ching-ju Lu, Michael E. Miller, Mark A. Espeland, Walter T. Ambrosius, William Applegate, Robert P. Byington, Delilah Cook, Curt D. Furberg, Lea N. Harvin, Leora Henkin, Med John Hepler, Fang-Chi Hsu, Laura Lovato, Wesley Roberson, Julia Rushing, Scott Rushing, Cynthia L. Stowe, Michael P. Walkup, Don Hire, W. Jack Rejeski, Jeffrey A. Katula, Peter H. Brubaker, Shannon L. Mihalko, Janine M. Jennings, Evan C. Hadley, Sergei Romashkan, Kushang V. Patel, Denise Bonds, Bonnie Spring, Joshua Hauser, Diana Kerwin, Kathryn Domanchuk, Rex Graff, Alvito Rego, Timothy S. Church, Steven N. Blair, Valerie H. Myers, Ron Monce, Nathan E. Britt, Melissa Nauta Harris, Ami Parks McGucken, Ruben Rodarte, Heidi K. Millet, Catrine Tudor-Locke, Ben P. Butitta, Sheletta G. Donatto, Shannon H. Cocreham, Abby C. King, Cynthia M. Castro, William L. Haskell, Randall S. Stafford, Leslie A. Pruitt, Kathy Berra, Veronica Yank, Roger A. Fielding, Miriam E. Nelson, Sara C. Folta, Edward M. Phillips, Christine K. Liu, Erica C. McDavitt, Kieran F. Reid, Dylan R. Kirn, Evan P. Pasha, Won S. Kim, Vince E. Beard, Eleni X. Tsiroyannis, Cynthia Hau, Stephen D. Anton, Susan Nayfield, Thomas W. Buford, Michael Marsiske, Bhanuprasad D. Sandesara, Jeffrey D. Knaggs, Megan S. Lorow, William C. Marena, Irina Korytov, Holly L. Morris, Margo Fitch, Floris F. Singletary, Jackie Causer, Katie A. Radcliff, Anne B. Newman, Stephanie A. Studenski, Bret H. Goodpaster, Nancy W. Glynn, Oscar Lopez, Neelesh K. Nadkarni, Kathy Williams, Mark A. Newman, George Grove, Janet T. Bonk, Jennifer Rush, Piera Kost, Diane G. Ives, Anthony P. Marsh, Tina E. Brinkley, Jamehl S. Demons, Kaycee M. Sink, Kimberly Kennedy, Rachel Shertzer-Skinner, Abbie Wrights, Rose Fries, Deborah Barr, Thomas M. Gill, Robert S. Axtell, Susan S. Kashaf, Nathalie de Rekeneire, Joanne M. McGloin, Karen C. Wu, Denise M. Shepard, Barbara Fennelly, Lynne P. Iannone, Raeleen Mautner, Theresa Sweeney Barnett, Sean N. Halpin, Matthew J. Brennan, Julie A. Bugaj, Maria A. Zenoni, Bridget M. Mignosa, Jeff Williamson, Hugh C. Hendrie, Stephen R. Rapp, Joe Verghese, Nancy Woolard, Mark Espeland, Janine Jennings, Valerie K. Wilson, Carl J. Pepine, Mario Ariet, Eileen Handberg, Daniel Deluca, James Hill, Anita Szady, Geoffrey L. Chupp, Gail M. Flynn, John L. Hankinson, Carlos A. Vaz Fragoso, Erik J. Groessl, and Robert M. Kaplan

Subjects
Male, medicine.medical_specialty, Waist, Blood lipids, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Lower risk, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Muscle Strength, Obesity, General Nursing, Abdominal obesity, Aged, Aged, 80 and over, Metabolic Syndrome, business.industry, Health Policy, General Medicine, Odds ratio, medicine.disease, Endocrinology, Female, Waist Circumference, Geriatrics and Gerontology, Metabolic syndrome, medicine.symptom, business, Body mass index
Abstract

Objective The purpose of this study was to examine the relationship between dynapenia and metabolic risk factors in obese and nonobese older adults. Methods A total of 1453 men and women (age ≥70 years) from the Lifestyle Interventions and Independence for Elders (LIFE) Study were categorized as (1) nondynapenic/nonobese (NDYN-NO), (2) dynapenic/nonobese (DYN-NO), (3) nondynapenic/obese (NDYN-O), or (4) dynapenic/obese (DYN-O), based on muscle strength (Foundation for the National Institute of Health criteria) and body mass index. Dependent variables were blood lipids, fasting glucose, blood pressure, presence of at least 3 metabolic syndrome (MetS) criteria, and other chronic conditions. Results A significantly higher likelihood of having abdominal obesity criteria in NDYN-NO compared with DYN-NO groups (55.6 vs 45.1%, P ≤ .01) was observed. Waist circumference also was significantly higher in obese groups (DYN-O = 114.0 ± 12.9 and NDYN-O = 111.2 ± 13.1) than in nonobese (NDYN-NO = 93.1 ± 10.7 and DYN-NO = 92.2 ± 11.2, P ≤ .01); and higher in NDYN-O compared with DYN-O ( P = .008). Additionally, NDYN-O demonstrated higher diastolic blood pressure compared with DYN-O (70.9 ± 10.1 vs 67.7 ± 9.7, P ≤ .001). No significant differences were found across dynapenia and obesity status for all other metabolic components ( P > .05). The odds of having MetS or its individual components were similar in obese and nonobese, combined or not with dynapenia (nonsignificant odds ratio [95% confidence interval]). Conclusion Nonobese dynapenic older adults had fewer metabolic disease risk factors than nonobese and nondynapenic older adults. Moreover, among obese older adults, dynapenia was associated with lower risk of meeting MetS criteria for waist circumference and diastolic blood pressure. Additionally, the presence of dynapenia did not increase cardiometabolic disease risk in either obese or nonobese older adults.

Published
2017

43. Changes in metabolic risk factors over 10 years and their associations with late-life cognitive performance: The Multi-Ethnic Study of Atherosclerosis

Author

Mark A. Espeland, Suzanne Craft, Alain G. Bertoni, Annette L. Fitzpatrick, Stephen R. Rapp, Laura D. Baker, Kaycee M. Sink, Rebecca F. Gottesman, Timothy M. Hughes, José A. Luchsinger, Erin D. Michos, Gregory L. Burke, and Kathleen M. Hayden

Subjects
Apolipoprotein E, medicine.medical_specialty, Diastole, Metabolic disorders, lcsh:Geriatrics, Cognitive Abilities Screening Instrument, lcsh:RC346-429, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Memory span, 030212 general & internal medicine, Effects of sleep deprivation on cognitive performance, lcsh:Neurology. Diseases of the nervous system, Diagnostic Assessment & Prognosis, Brain, Cognition, Cognitive test, Psychiatry and Mental health, lcsh:RC952-954.6, Blood pressure, Metabolism, Physical therapy, Neurology (clinical), Cognitive function, Psychology, 030217 neurology & neurosurgery
Abstract

Background We examined whether changes in metabolic factors over 10 years were associated with cognitive performance. Methods Participants from the Multi-Ethnic Study of Atherosclerosis were followed since baseline (2000–2002) with five clinical examinations. At exam 5 (2010–2012), they received a short cognitive battery (Cognitive Abilities Screening Instrument [CASI], Digit Symbol Coding [DSC], and Digit Span [DS]). We examined associations between baseline metabolic factors and their changes over time before cognitive testing. Results Among 4392 participants, baseline metabolic disorders (fasting glucose, systolic and diastolic blood pressures) were significantly associated with poorer CASI, DSC, and DS scores measured 10 years later. Increases in blood pressure were associated with lower cognitive performance. Results did not differ by race/ethnicity and were stronger among those without the APOE e4 allele. Conclusions Cognitive performance was associated with antecedent abnormalities in glucose metabolism and blood pressure increases. Findings appeared stronger among APOE e4-negative participants.

Published
2017

44. Alcohol Consumption and Risk of Dementia and Cognitive Decline Among Older Adults With or Without Mild Cognitive Impairment

Author

Kenneth J. Mukamal, Richard L. Nahin, Kaycee M Sink, Rachel H. Mackey, Annette L. Fitzpatrick, Stephen R. Rapp, Jeff D. Williamson, Lewis H. Kuller, Majken K. Jensen, Manja Koch, Oscar L. Lopez, and Steven T. DeKosky

Subjects
Male, medicine.medical_specialty, Alcohol Drinking, Apolipoprotein E4, Drinking Behavior, Neuropsychological Tests, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Interquartile range, Internal medicine, medicine, Dementia, Humans, Cognitive Dysfunction, 030212 general & internal medicine, Prospective Studies, Cognitive decline, Prospective cohort study, Original Investigation, Aged, Proportional Hazards Models, Aged, 80 and over, Proportional hazards model, business.industry, Research, Hazard ratio, General Medicine, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Online Only, Neurology, Female, business, 030217 neurology & neurosurgery, Algorithms, Cohort study
Abstract

Key Points Question Is alcohol consumption associated with the risk of dementia and cognitive decline in older adults with or without mild cognitive impairment? Findings In this cohort study of 3021 participants aged 72 years and older, alcohol intake within recommended limits was not significantly associated with a lower risk of dementia among participants with or without mild cognitive impairment at baseline. Among participants without mild cognitive impairment, daily low-quantity drinking was associated with lower dementia risk compared with infrequent higher-quantity drinking. Meaning These findings suggest that physicians caring for older adults need to carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about their alcohol consumption., This cohort study examines the association between alcohol intake and risk of dementia among older adults with or without mild cognitive impairment., Importance Substantial heterogeneity and uncertainty exist in the observed associations between alcohol consumption and dementia. Objective To assess the association between alcohol consumption and dementia and the roles of mild cognitive impairment (MCI) and apolipoprotein E ε4 (APOE E4) genotype in modifying this association. Design, Setting, and Participants This cohort study used data from the Ginkgo Evaluation of Memory Study, conducted from 2000 to 2008 among US community-dwelling participants. This study analyzed 3021 participants aged 72 years and older who were free of dementia. Data analysis was performed from 2017 to 2018. Exposures Self-reported alcohol consumption, drinking frequency, and quantity. Main Outcomes and Measures Using multivariable proportional hazards regression and linear mixed models, the risk of dementia and the rate of change over time in the Modified Mini-Mental State Examination were estimated. Results Among 3021 participants, the median (interquartile range) age was 78 (76-80) years; 1395 (46.2%) were female. During a median (interquartile range) follow-up of 6.0 (4.9-6.5) years, 512 cases of dementia occurred. For 7.1 to 14.0 drinks per week compared with less than 1.0 drink per week, the hazard ratios for dementia were 0.63 (95% CI, 0.38-1.06) among 2548 participants without MCI and 0.93 (95% CI, 0.47-1.84) among 473 participants with MCI. Among participants with MCI, the hazard ratio for dementia was 1.72 (95% CI, 0.87-3.40) for more than 14.0 drinks per week compared with less than 1.0 drink per week. The association of alcohol intake with dementia differed for participants with and without baseline MCI (P for interaction = .03). Among participants without MCI, daily low-quantity drinking was associated with lower dementia risk than infrequent higher-quantity drinking (hazard ratio, 0.45; 95% CI, 0.23-0.89; P = .02). Findings were consistent when stratified by sex, age, and APOE E4 genotype. Compared with drinking less than 1.0 drink per week, complete abstention (in participants without MCI) and the consumption of more than 14.0 drinks per week (in participants with MCI) were associated with lower Modified Mini-Mental State Examination scores (mean difference at follow-up compared with baseline, −0.46 point [95% CI, −0.87 to −0.04 point] and −3.51 points [95% CI, −5.75 to −1.27 points], respectively). Conclusions and Relevance In this study, complete abstention and consuming more than 14.0 drinks per week (compared with drinking

Published
2019

45. P1‐046: BASELINE CHARACTERISTICS FROM CREAD2: A PHASE III TRIAL OF CRENEZUMAB IN EARLY (PRODROMAL‐TO‐MILD) ALZHEIMER'S DISEASE

Author

Susanne Ostrowitzki, Reina N. Fuji, Paulo Fontoura, Angelica Quartino, Michael Rabbia, Andres Schneider, Howard Mackey, Jillian Smith, Kaycee M. Sink, Francis Warren, Susan Yule, and Rachelle S. Doody

Subjects
medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Baseline characteristics, Internal medicine, Phase (matter), Crenezumab, medicine, Cardiology, Neurology (clinical), Geriatrics and Gerontology, business
Published
2019

46. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial

Author

Jennifer Martindale-Adams, Alfred K. Cheung, Gordon J. Chelune, Carolyn H Still, Linda O. Nichols, Meng-Kang Hsieh, Michael Crowe, Daniel E. Weiner, Sarah A. Gaussoin, Jeff D. Williamson, Maryjo Cleveland, Clinton B. Wright, Lenore J. Launer, William C. Cushman, R. Nick Bryan, Darrin Harris, Claudia S. Moy, Manjula Kurella Tamura, Mahboob Rahman, Alan J. Lerner, Jackson T. Wright, Cora E. Lewis, Jennifer Walker, Virginia G. Wadley, Karen C. Johnson, Paul K. Whelton, Paula Ogrocki, Valerie M. Wilson, Guray Erus, Mark A. Supiano, Nancy Woolard, Alexander P. Auchus, Joni K. Snyder, Larry J. Fine, Ilya M. Nasrallah, Stephen R. Rapp, Kaycee M. Sink, Lisa Desiderio, Paul L. Kimmel, Nicholas M. Pajewski, David M. Reboussin, Christos Davatzikos, Jeffrey A. Cutler, Suzanne Oparil, Laura H. Coker, Bonnie C. Sachs, and Michael V. Rocco

Subjects
Male, medicine.medical_specialty, Randomization, Blood Pressure, 01 natural sciences, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Dementia, Humans, Cognitive Dysfunction, 030212 general & internal medicine, 0101 mathematics, Stroke, Antihypertensive Agents, Aged, Proportional Hazards Models, Aged, 80 and over, business.industry, Standard treatment, 010102 general mathematics, Hazard ratio, General Medicine, Middle Aged, medicine.disease, Blood pressure, Cardiovascular Diseases, Ambulatory, Hypertension, Female, business, Follow-Up Studies
Abstract

Importance There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration ClinicalTrials.gov Identifier:NCT01206062

Published
2019

47. APOE Genotypes Associate With Cognitive Performance but Not Cerebral Structure: Diabetes Heart Study MIND

Author

Laura M. Raffield, Donald W. Bowden, Jeff D. Williamson, S. Carrie Smith, Benjamin C. Wagner, Fang-Chi Hsu, Jianzhao Xu, Christopher T. Whitlow, Joycelyn C Hardy, Barry I. Freedman, Nicholette Allred, Joseph A. Maldjian, Christina E. Hugenschmidt, Kaycee M. Sink, and Jasmin Divers

Subjects
Research design, Gerontology, Apolipoprotein E, Male, Heterozygote, Genotype, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Neuropsychological Tests, 03 medical and health sciences, 0302 clinical medicine, Apolipoproteins E, Cognition, Memory, Diabetes mellitus, Internal Medicine, medicine, Dementia, Humans, 030212 general & internal medicine, Effects of sleep deprivation on cognitive performance, Epidemiology/Health Services Research, Genetic Association Studies, Aged, Advanced and Specialized Nursing, business.industry, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, business, Cognition Disorders, 030217 neurology & neurosurgery
Abstract

OBJECTIVE Dementia is a debilitating illness with a disproportionate burden in patients with type 2 diabetes (T2D). Among the contributors, genetic variation at the apolipoprotein E locus (APOE) is posited to convey a strong effect. This study compared and contrasted the association of APOE with cognitive performance and cerebral structure in the setting of T2D. RESEARCH DESIGN AND METHODS European Americans from the Diabetes Heart Study (DHS) MIND (n = 754) and African Americans from the African American (AA)-DHS MIND (n = 517) were examined. The cognitive battery assessed executive function, memory, and global cognition, and brain MRI was performed. RESULTS In European Americans and African Americans, the APOE E4 risk haplotype group was associated with poorer performance on the modified Mini-Mental Status Examination (P < 0.017), a measure of global cognition. In contrast to the literature, the APOE E2 haplotype group, which was overrepresented in these participants with T2D, was associated with poorer Rey Auditory Verbal Learning Test performance (P < 0.032). Nominal associations between APOE haplotype groups and MRI-determined cerebral structure were observed. CONCLUSIONS Compared with APOE E3 carriers, E2 and E4 carriers performed worse in the cognitive domains of memory and global cognition. Identification of genetic contributors remains critical to understanding new pathways to prevent and treat dementia in the setting of T2D.

Published
2016

48. APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume

Author

Alan J. Lerner, S. Carrie Smith, Mohammad Salehi Sadaghiani, Christopher T. Whitlow, Jeffrey T. Bates, Barry I. Freedman, Jackson T. Wright, Michael V. Rocco, Dominic S. Raj, Jasmin Divers, Crystal A. Gadegbeku, R. Nick Bryan, Benjamin C. Wagner, Joseph A. Maldjian, Carl D. Langefeld, Nicholette D. Palmer, Jianzhao Xu, Nicholas M. Pajewski, Pamela J. Hicks, Kaycee M. Sink, Donald W. Bowden, Amret T. Hawfield, Robert D. Toto, Jeff D. Williamson, and Lijun Ma

Subjects
Risk, medicine.medical_specialty, Renal function, Blood Pressure, 030204 cardiovascular system & hematology, Kidney Function Tests, Article, White matter, 03 medical and health sciences, chemistry.chemical_compound, Cognition, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Genetic model, medicine, Humans, Gray Matter, Randomized Controlled Trials as Topic, Creatinine, medicine.diagnostic_test, business.industry, Brain, Magnetic resonance imaging, Apolipoprotein L1, medicine.disease, Magnetic Resonance Imaging, White Matter, Black or African American, Apolipoproteins, Endocrinology, Blood pressure, medicine.anatomical_structure, Diabetes Mellitus, Type 2, chemistry, Cardiovascular Diseases, Nephrology, Cerebral Small Vessel Diseases, Hypertension, Cardiology, Kidney Diseases, Lipoproteins, HDL, business, Body mass index, 030217 neurology & neurosurgery, Glomerular Filtration Rate
Abstract

To assess apolipoprotein L1 gene ( APOL1 ) renal-risk-variant effects on the brain, magnetic resonance imaging (MRI)-based cerebral volumes and cognitive function were assessed in 517 African American–Diabetes Heart Study (AA-DHS) Memory IN Diabetes (MIND) and 2568 hypertensive African American Systolic Blood Pressure Intervention Trial (SPRINT) participants without diabetes. Within these cohorts, 483 and 197 had cerebral MRI, respectively. AA-DHS participants were characterized as follows: 60.9% female, mean age of 58.6 years, diabetes duration 13.1 years, estimated glomerular filtration rate of 88.2 ml/min/1.73 m 2 , and a median spot urine albumin to creatinine ratio of 10.0 mg/g. In additive genetic models adjusting for age, sex, ancestry, scanner, intracranial volume, body mass index, hemoglobin A1c, statins, nephropathy, smoking, hypertension, and cardiovascular disease, APOL1 renal-risk-variants were positively associated with gray matter volume (β = 3.4 × 10 –3 ) and negatively associated with white matter lesion volume (β = –0.303) (an indicator of cerebral small vessel disease) and cerebrospinal fluid volume (β= –30707) (all significant), but not with white matter volume or cognitive function. Significant associations corresponding to adjusted effect sizes (β/SE) were observed with gray matter volume (0.16) and white matter lesion volume (–0.208), but not with cerebrospinal fluid volume (–0.251). Meta-analysis results with SPRINT Memory and Cognition in Decreased Hypertension (MIND) participants who had cerebral MRI were confirmatory. Thus, APOL1 renal-risk-variants are associated with larger gray matter volume and lower white matter lesion volume suggesting lower intracranial small vessel disease.

Published
2016

49. COGNITIVE PERFORMANCE DOES NOT LIMIT PHYSICAL ACTIVITY PARTICIPATION IN THE LIFESTYLE INTERVENTIONS AND INDEPENDENCE FOR ELDERS PILOT STUDY (LIFE-P)

Author

F. Kramer, Abby C. King, Roger A. Fielding, Kieran F. Reid, Robert S. Axtell, Joe Verghese, Valerie H. Myers, Kaycee M Sink, Michael P. Walkup, Diana R. Kerwin, Jeffery A. Katula, Caterina Rosano, Jeff D. Williamson, Stephen D. Anton, Michael Miller, Stephanie A. Studenski, and Oscar L. Lopez

Subjects
Male, Gerontology, medicine.medical_specialty, Pilot Projects, Neuropsychological Tests, Article, law.invention, Cognition, Randomized controlled trial, law, medicine, Humans, Cognitive Dysfunction, Single-Blind Method, Cognitive skill, Effects of sleep deprivation on cognitive performance, Mobility Limitation, Exercise, Health Education, Aged, Aged, 80 and over, Psychomotor learning, Successful aging, Working memory, Flexibility (personality), Exercise Therapy, Memory, Short-Term, Physical therapy, Patient Compliance, Female, Sedentary Behavior, Psychology
Abstract

Objectives: We examined whether multiple domains of baseline cognitive performance were associated with prospective physical activity (PA) adherence in the Lifestyle Interventions and Independence for Elders Pilot study (LIFE-P). Design, Setting, Participants: The LIFE-P study was a single-blind, multicenter, randomized controlled trial of a PA intervention compared to a successful aging educational intervention in sedentary, mobility-limited older adults. Intervention: A 12-month structured, moderate-intensity, multi-modal PA program that included walking, resistance training, and flexibility exercises. For the first 2 months (adoption), 3 center-based exercise sessions (40–60 min) / week were conducted. During the next 4 months (transition), center-based sessions were conducted 2 times / week. The subsequent maintenance phase consisted of optional once-to-twice-per-week center-based sessions and home-based PA. Measurements: Tests of executive and global cognitive functioning, working memory and psychomotor speed were administered at baseline. Median test scores were used to dichotomize participants into low or high cognitive performance groups. Results: 52 mobility-limited older adults (age: 76.9 ±5 yrs) were randomized to the PA arm of LIFE-P. Compared to participants with high cognitive performance, participants with low performance had similar PA adherence rates (all P ≥ 0.34). Furthermore, weak and non-significant univariate relationships were elicited between all measures of cognition and overall PA adherence levels (r values ranged: -0.20 to 0.12, P ≥ 0.12). Conclusion: These data suggest that cognitive performance does not limit long-term PA adherence in mobility-limited older adults. Additional studies in larger cohorts are warranted to verify these findings.

Published
2016

50. P4‐209: A PUBLIC RESOURCE OF BASELINE DATA FROM THE API AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE COLOMBIA TRIAL

Author

Nan Hu, Heather Guthrie, Yakeel T. Quiroz, Sergio Alvarez, Jessica B. Langbaum, Kewei Chen, Ronald G. Thomas, Katie L. Knoll, Eric M. Reiman, Silvia Rios Romenets, Jillian Smith, Arthur W. Toga, Kaycee M Sink, Pierre N. Tariot, Connie A. Boker, Francisco Lopera, and William Cho

Subjects
Epidemiology, business.industry, Health Policy, Baseline data, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Demography, Public resource
Published
2018

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