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1. Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study

Author: Emily D. Clark, Jamie Perin, Nathan Herrmann, Olga Brawman‐Mintzer, Krista L. Lanctôt, Alan J. Lerner, Jacobo Mintzer, Prasad R. Padala, Paul B. Rosenberg, Susie Sami, David M. Shade, Christopher H. vanDyck, Anton P. Porsteinsson, and for the ADMET‐2 Study Group
Subjects: agitation, Alzheimer's disease, central nervous system stimulant, methylphenidate, Neuropsychiatric Inventory, neuropsychiatric symptoms, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract INTRODUCTION Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire. HIGHLIGHTS Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy. Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6‐month treatment period compared to placebo. Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.
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. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial

Author: Roberta W. Scherer, Lea Drye, Jacobo Mintzer, Krista Lanctôt, Paul Rosenberg, Nathan Herrmann, Prasad Padala, Olga Brawman-Mintzer, William Burke, Suzanne Craft, Alan J. Lerner, Allan Levey, Anton Porsteinsson, Christopher H. van Dyck, and the ADMET 2 Research Group
Subjects: Medicine (General), R5-920
Abstract: Abstract Background Alzheimer’s disease (AD) is characterized not only by cognitive and functional decline, but also often by the presence of neuropsychiatric symptoms. Apathy, which can be defined as a lack of motivation, is one of the most prevalent neuropsychiatric symptoms in AD and typically leads to a worse quality of life and greater burden for caregivers. Treatment options for apathy in AD are limited, but studies have examined the use of the amphetamine, methylphenidate. The Apathy in Dementia Methylphenidate Trial (ADMET) found that treatment of apathy in AD with methylphenidate was associated with significant improvement in apathy in two of three outcome measures, some evidence of improvement in global cognition, and minimal adverse events. However, the trial only enrolled 60 participants who were followed for only 6 weeks. A larger, longer-lasting trial is required to confirm these promising findings. Methods The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a phase III, placebo-controlled, masked, 6-month, multi-center, randomized clinical trial targeted to enroll 200 participants with AD and apathy. Participants are randomly assigned 1:1 to 20 mg methylphenidate per day prepared as four over-encapsulated tablets or to matching placebo. The primary outcomes include (1) the mean difference in the Neuropsychiatric Inventory Apathy subscale scores measured as change from baseline to 6 months, and (2) the odds of having a given rating or better on the modified AD Cooperative Study Clinical Global Impression of Change ratings at month 6 compared with the baseline rating. Other outcomes include change in cognition, safety, and cost-effectiveness measured at monthly follow-up visits up to 6 months. Discussion Given the prevalence of apathy in AD and its impact on both patients and caregivers, an intervention to alleviate apathy would be of great benefit to society. ADMET 2 follows on the promising results from the original ADMET to evaluate the efficacy of methylphenidate as a treatment for apathy in AD. With a larger sample size and longer follow up, ADMET 2 is poised to confirm or refute the original ADMET findings. Trial registration ClinicalTrials.gov, NCT02346201 . Registered on 26 January 2015.
Published: 2018
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4. 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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5. Lifestyle Choices and Brain Health

Author: Jacobo Mintzer, Keaveny Anne Donovan, Arianne Zokas Kindy, Sarah Lenz Lock, Lindsay R. Chura, and Nicholas Barracca
Subjects: brain health, geriatrics, lifestyle, prevention, dementia, cognitive decline, Medicine (General), R5-920
Abstract: This article is largely based on the recommendations of the AARP's Global Council on Brain Health (GCBH) and aims to provide an overview of evidence from current literature and expert opinion on key elements known to be relevant in preserving brain health as people age. Although we realize that there may be other lifestyle choices of importance to brain health, the GCBH has decided to initially focus on the issues below based on the preferences and concerns of its members. The areas to be discussed are: mental well-being, exercise, cognitively stimulating activities, sleep, nutrition, and social connectedness. Our review concluded that each of these areas offer opportunities for aging individuals to make lifestyle adjustments to positively impact brain health.
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. 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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11. 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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12. Escitalopram for agitation in Alzheimer's disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial

Author: Lyketsos, Constantine G., Porsteinsson, Anton P., Avramopoulos, Dimitri, Munro, Cynthia, Lee, Hochang, Bienko, Nicholas, Shade, Dave, Ehrhardt, Stephan, Jones, Jennifer, Casper, Anne Shanklin, Frangakis, Constantine, Lears, Andy, Baksh, Sheriza, Perin, Jamie, Ryan, Laurie, McKelvy, Alvin D., Rosenberg, Paul, Nowrangi, Milap, Lawrence, Sarah, Schultz, Meghan, Jamil, Nimra, Devanand, D.P., Simon-Pearson, Laura, Pelton Jacobo Mintzer, Gregory, Brawman-Mintzer, Olga, Williams, Arthur, Awkar, Anthony, Keltz, Melanie, Kowalski, Nancy, Lane, Kaitlyn, Martin, Kim, Salem-Spencer, Susan, Widman, Asa, Pollock, Bruce G., Kumar, Sanjeev, Lourenco, Lillian, Mulsant, Benoit H., Lago, Kyle, Rajji, Tarek K., Schneider, Lon S., Becerra, Maurcio, Dagerman, Karen, Pawluczyk, Sonia, Teodoro, Liberty, Munro, Cynthia A., Rosenberg, Paul B., Devanand, Davangere P., Mintzer, Jacobo, Ismail, Zahinoor, Baksh, Sheriza N., Drye, Lea T., and Shade, David M.
Published: 2019
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13. Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2)

Author: Krista L. Lanctôt, Clara Chen, Ethan Mah, Alex Kiss, Abby Li, Dave Shade, Roberta W. Scherer, Danielle Vieira, Hamadou Coulibaly, Paul B. Rosenberg, Alan J. Lerner, Prasad R. Padala, Olga Brawman-Mintzer, Christopher H. van Dyck, Anton P. Porsteinsson, Suzanne Craft, Allan Levey, William J. Burke, Jacobo Mintzer, and Nathan Herrmann
Subjects: Psychiatry and Mental health, Clinical Psychology, Geriatrics and Gerontology, Gerontology
Abstract: Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. Results: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). Discussion: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer’s disease while considering the burden on the healthcare system.
Published: 2023

14. Agitation in cognitive disorders: Progress in the International Psychogeriatric Association consensus clinical and research definition

Author: Mary Sano, Jeffrey Cummings, Stefanie Auer, Sverre Bergh, Corinne E. Fischer, Debby Gerritsen, George Grossberg, Zahinoor Ismail, Krista Lanctôt, Maria I. Lapid, Jacobo Mintzer, Rebecca Palm, Paul B. Rosenberg, Michael Splaine, Kate Zhong, and Carolyn W. Zhu
Subjects: Psychiatry and Mental health, Clinical Psychology, Geriatrics and Gerontology, Gerontology
Abstract: Background: The International Psychogeriatric Association (IPA) published a provisional consensus definition of agitation in cognitive disorders in 2015. As proposed by the original work group, we summarize the use and validation of criteria in order to remove “provisional” from the definition. Methods: This report summarizes information from the academic literature, research resources, clinical guidelines, expert surveys, and patient and family advocates on the experience of use of the IPA definition. The information was reviewed by a working group of topic experts to create a finalized definition. Results: We present a final definition which closely resembles the provisional definition with modifications to address special circumstances. We also summarize the development of tools for diagnosis and assessment of agitation and propose strategies for dissemination and integration into precision diagnosis and agitation interventions. Conclusion: The IPA definition of agitation captures a common and important entity that is recognized by many stakeholders. Dissemination of the definition will permit broader detection and can advance research and best practices for care of patients with agitation.
Published: 2023

15. Reduction and prevention of agitation in persons with neurocognitive disorders: an international psychogeriatric association consensus algorithm

Author: Jeffrey Cummings, Mary Sano, Stefanie Auer, Sverre Bergh, Corinne E. Fischer, Debby Gerritsen, George Grossberg, Zahinoor Ismail, Krista Lanctôt, Maria I. Lapid, Jacobo Mintzer, Rebecca Palm, Paul B. Rosenberg, Michael Splaine, Kate Zhong, and Carolyn W. Zhu
Subjects: Psychiatry and Mental health, Clinical Psychology, Geriatrics and Gerontology, Gerontology
Abstract: Objectives To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA) Design: Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion Setting: IPA Agitation Workgroup Participants: IPA panel of international experts on agitation Intervention: Integration of available information into a comprehensive algorithm Measurements: None Results The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues—home, nursing home, emergency department, hospice—and adjustments to the therapeutic approach are presented. Conclusions The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.
Published: 2023

16. Dementia in the incarcerated population: a retrospective study using the South Carolina Alzheimer’s disease registry, USA

Author: Margaret Chandlee Miller, Glaucia Salgado, Nicole Nasrallah, Jennifer Bronson, Charles P. Sabatino, and Jacobo Mintzer
Subjects: Health Professions (miscellaneous)
Abstract: Purpose Research about the prevalence of dementia among older adults in the incarceration system is currently lacking, and further investigation is warranted. Considering the high level of healthcare needs, unique behavioural issues and difficulty to rehabilitate within the system due to its punitive approach and lack of effective rehabilitation programs, further investigation is warranted to characterize and determine the number of incarcerated older adults with dementia. The purpose of this study is to estimate the prevalence of individuals with dementia in the prison system while also describing the incarceration, demographic and offence-related characteristics of this unique population. Design/methodology/approach South Carolina (SC) Alzheimer’s Disease and Related Dementias Registry (1992–2016) and South Carolina Department of Corrections (SCDC) data (Fiscal years 1992–2019) were cross-referenced. The prevalence of Alzheimer’s disease and related dementias (ADRD) cases in the corrections system was calculated using South Carolina Alzheimer's Disease (SC AD) SC ADRD Registry and SCDC data. Pearson’s correlation coefficients were calculated to determine strength and direction of relationships between year of incarceration and frequency of ADRD cases both prior to and after incarcerations, respectively. Significant differences by age group, race, gender and dementia type were determined using a two-tailed pooled t-test and Bonferroni approach where appropriate. Count data for types of crimes committed are also presented. Findings The linkage showed that there were 2,171 individuals within the SC AD Registry who have been in the corrections system, about 1% of those in the Registry. Of these individuals, 1,930 cases were diagnosed with ADRD after incarceration and 241 prior to incarceration. In 2016, 317 individuals with ADRD were incarcerated. For ages 55 and above in South Carolina, the prevalence of ADRD is 6.7% in the general, non-incarcerated population compared to 14.4% in the incarcerated population. Additional results showed that those diagnosed with ADRD between 55 and 65 years of age had a significantly lower mean age at first incarceration (34.6 years of age) than those diagnosed between 66 and 74 years of age (55.9 years of age), indicating that those incarcerated earlier in life had an earlier dementia diagnosis. Additionally, African Americans had a significantly lower mean age at first incarceration (43.4 years of age) than Whites (46.2 years of age) and females had significantly lower mean age at first incarceration (42.9 years of age) than males (45 years of age). When investigating trends, results showed a significant positive linear association between year and frequency of ADRD diagnoses (p-value < 0.05) for those with ADRD diagnosis prior to incarceration and a significant decreasing linear association (p-value < 0.0001) in the number of individuals with an ADRD diagnosis after corrections. Findings also showed that a large percentage of older adults with ADRD in prison did not commit a violence offence. Originality/value This study links a population-based Alzheimer’s disease registry and state-wide corrections data to estimate the prevalence of individuals with dementia in the prison system. This linkage presents an opportunity to fill in significant gaps and contribute to the body of literature on dementia among people in prison in the USA.
Published: 2023

17. ALUMNI AD Study Design: Evaluation of Subcutaneous Gantenerumab in Historically Underrepresented US Populations With Early Symptomatic Alzheimer’s Disease (S26.006)

Author: Sheila Seleri, Sharon Brangman, J. Neil Henderson, Monica Parker, Stephanie Monroe, Jacobo Mintzer, Alexandria Wise-Brown, Michael Grundman, Janice Smith, Rachelle Doody, Helen Lin, Beverly Assman, and Gregory Rippon
Published: 2023

18. Correlation between changes in apathy and global cognition in apathetic associated with Alzheimer's disease: analysis of the Apathy Dementia Methylphenidate 2 (ADMET 2) clinical trial

Author: Krista Lanctôt, Krushnaa Sankhe, Jamie Perin, Nathan Herrmann, Olga Brawman-Mintzer, Alan J. Lerner, Jacobo Mintzer, Prasad R. Padala, Paul B. Rosenberg, David M. Shade, Christopher H. van Dyck, and Anton P. Porsteinsson
Subjects: Psychiatry and Mental health, Geriatrics and Gerontology
Published: 2023

19. Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial

Author: Hal S. Wortzel, Mark B. Hamner, Marcel Bizien, Tom Sindowski, Philip D. Harvey, Ricardo E. Jorge, Murray A. Raskind, X. Charlene Tang, Mercedes Rodriguez-Suarez, Yongliang Wei, Michael David Horner, Suzanne McGarity, Keaveny Anne Donovan, Jacobo Mintzer, Domenic J. Reda, Lisa Johnson-Greene, David B. Arciniegas, Olga Brawman-Mintzer, R Jared Martineau, and Arianne Zokas Kindy
Subjects: Adult, Male, Transdermal patch, Traumatic brain injury, Transdermal Patch, Rivastigmine, law.invention, Cohort Studies, Double-Blind Method, Randomized controlled trial, law, Brain Injuries, Traumatic, Humans, Medicine, Cognitive Dysfunction, Treatment Failure, Cognitive impairment, health care economics and organizations, Veterans, business.industry, Cognition, Middle Aged, medicine.disease, humanities, Clinical trial, Anesthesia, Cholinergic, Female, Cholinesterase Inhibitors, Neurology (clinical), business, medicine.drug
Abstract: Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm
Published: 2021

20. Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial

Author: Carl Chiang, Jacquelynn Copeland, Vanessa Raymont, Peter Connelly, Reto Kressig, Guy G. Potter, Daniel K. Burns, Stephen Pearson, Manish Saxena, Ann M. Saunders, Debra Fleischman, DeRen Huang, Thomas Leyhe, Gabriel Leger, Gigi Lefebvre, Mardik Donikyan, Natalie Denburg, Alex Knopman, Nancy Voight, James Burke, Philip Moore, James R. Burke, Margaret Newson, Stephen Haneline, Adam J. Schwarz, George Demakis, Joseph Butchart, Robert Mitchell, Mark Leibowitz, Michael Woodward, Robert Alexander, Concetta Forchetti, Emiliangelo Ratti, Andreas U. Monsch, Lon S. Schneider, Aaron Ritter, Joscelyn Agron-Figueroa, Fraser Inglis, Craig Curtis, Judith Neugroschl, Geraint Price, Mark Brody, Clark Johnson, Clive Ballard, Stephen Thein, Meredith Culp, Kristine Yaffe, Ahad Sabet, Walter Braude, Gregory Kirk, David Krefetz, Rupert Noad, Omid Omidvar, John Sass, Brenda L. Plassman, James Bergthold, Arne Klostermann, Haydn Till, Aaron Ellenbogen, Patrick Harrigan, Heinz-Peter Herbst, Joseph Kass, Lorna Wallace, Jennifer Robinson, Elliot Henderson, Felicia Goldstein, Christopher McWilliam, R. Clarnette, Jerry Halsten, Dan Rujescu, Silvana Micallef, Nestor Galvez-Jimenez, Jeffrey Ross, Dag Aarsland, Hugh Miller, Theresa Campbell, Jingtao Wu, Allan Levey, Liebhild Stratmann, Rosalyn Lai, Agnes Flöel, Richard Shingleton, Steve Higham, Pierre N. Tariot, Esteban Olivera, Sandra Carusa, Amanda Olley, Ricky Mofsen, Kathryn Goozee, Kara Lyons, Richard J. Brown, Marwan N. Sabbagh, Virginia De Sanctis, Jerome Goldstein, Hamid R. Sohrabi, Lefkos T. Middleton, Eugen Schlegel, Donna Munic-Miller, Sylvia Robinson, David Watson, Oda Ackermann, Ralph Votolato, Peter Bailey, Paul Massman, Daniel Gruener, Robert Perneczky, Frederick Schaerf, Craig W. Ritchie, Scott Losk, Christina Zimmerman, Mario Parra, Jill Crusey, Edward Zamrini, Christine Belden, Thomas Arnold, Alexander White, Linda Rice, Elizabeth Coulthard, Jane Martin, Anne Koplin, Rebecca Evans, Janet O'Neil, Oliver Peters, Raj Shah, Marshall Nash, Ronald Bradley, Kathleen A. Welsh-Bohmer, Howard Hassman, Scott Barton, Robert Cohen, Robert Stephenson, Jacobo Mintzer, Michael W. Lutz, Wendy Bond, Rachelle S. Doody, Ronald Hofner, and Laura Samson
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Population, Placebo-controlled study, Placebo, Risk Assessment, Biomarkers, Pharmacological, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Alzheimer Disease, Risk Factors, law, Internal medicine, medicine, Humans, Cognitive Dysfunction, Adverse effect, education, Aged, Aged, 80 and over, education.field_of_study, Pioglitazone, business.industry, Hazard ratio, Prognosis, Clinical trial, Treatment Outcome, 030104 developmental biology, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.
Published: 2021

21. Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer’s disease (MCI and dementia) in primary care: a review and synthesis

Author: Richard G. Stefanacci, S. Seleri Assunção, J. Susman, S. A. Brunton, C. K. Clevenger, W. C. Jackson, S. F. Candela, Alireza Atri, Jacobo Mintzer, Valerie T. Cotter, Devangere P. Devanand, Marwan N. Sabbagh, Howard Fillit, Gary W. Small, Jeffrey L. Cummings, George T. Grossberg, David S. Geldmacher, A. Wise-Brown, Diana R. Kerwin, J. L. Liss, and Tobias Bittner
Subjects: 0301 basic medicine, medicine.medical_specialty, Time Factors, Early signs, media_common.quotation_subject, Disease, Primary care, 030204 cardiovascular system & hematology, Appropriate use, 03 medical and health sciences, 0302 clinical medicine, Optimism, Alzheimer Disease, Internal Medicine, Humans, Medicine, Dementia, Intensive care medicine, media_common, Primary Health Care, business.industry, Cognition, medicine.disease, 030104 developmental biology, Alzheimer's disease, business
Abstract: The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.
Published: 2021

22. Cost Consequence Analysis of ADMET 2

Author: Ethan Mah, Krista Lanctôt, Qi Zhen Chen, Dave Shade, Roberta Scherer, Danielle Vieira, Hamadou Coulibaly, Paul Rosenberg, Alan Lerner, Prasad Padala, Olga Brawman-Mintzer, Christopher van Dyck, Anton Porsteinsson, Jacobo Mintzer, and Nathan Herrmann
Subjects: Psychiatry and Mental health, Geriatrics and Gerontology
Published: 2023

23. POTENTIAL BENEFITS OF THC AND CBD IN THE TREATMENT OF HOSPICE-ELIGIBLE DEMENTED AND AGITATED PATIENTS

Author: Jacobo` Mintzer
Subjects: Health (social science), Life-span and Life-course Studies, Health Professions (miscellaneous)
Abstract: Today, half of the patients suffering from Alzheimer’s disease (AD) will use hospice care in the last days of their life. Most of them will present with moderate to severe agitation. In the absence of evidence-based guidelines, Hospice care eligible patients with Agitation and Alzheimer’s disease (AD) or other types of Dementia (HAD) are treated with a combination of antipsychotics, benzodiazepines, and opiates, which generate a variety of side effects. Two cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), appear to be promising therapies for agitation in HAD with minimal side effects. Specifically, we suggest that a combination of THC and CBD oils have enhanced synergistic effects while maintaining a low side effect profile that the combination may provide. The evidence for this hypothesis will be discussed during the symposium.
Published: 2022

24. ADRD as Additional Risk Factor for Adverse Events Among Opioid-Using Older Adults

Author: Corey Hassell, Jacobo Mintzer, Margaret Miller, Mindi Spencer, Nicole Nasrallah, and Jessica Broadway
Subjects: Psychiatry and Mental health, Geriatrics and Gerontology
Published: 2022

25. Diagnostic criteria for apathy in neurocognitive disorders

Author: Alan J. Lerner, Steven T. DeKosky, Zahinoor Ismail, Paul B. Rosenberg, Hans J. Moebius, Moyra E. Mortby, Daniel R. Bateman, Anton P. Porsteinsson, Abby Li, Krista L. Lanctôt, David Miller, Jacobo Mintzer, Lawrence Adler, Jeffrey L. Cummings, Mary Sano, Philippe Robert, Constantine G. Lyketsos, Judith Jaeger, Corinne E. Fischer, Myuri Ruthirakuhan, Valeria Manera, Didier Meulien, Stephane Pollentier, Carla Zucchero Sarracini, Masud Husain, Larry Ereshefsky, and Jill Rasmussen
Subjects: medicine.medical_specialty, Consensus, Delphi Technique, Epidemiology, Apathy, Emotions, Neurocognitive Disorders, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, medicine, Humans, Emotional expression, Psychiatry, Expert Testimony, Motivation, 030214 geriatrics, business.industry, Health Policy, Cognition, Expert group, Clinical trial, Psychiatry and Mental health, Etiology, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, Construct (philosophy), Neurocognitive, 030217 neurology & neurosurgery
Abstract: Introduction Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. Methods The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. Results The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. Discussion These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.
Published: 2021

26. Brain amyloid burden, sleep, and 24-hour rest/activity rhythms: screening findings from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Studies

Author: Paul S. Aisen, Gad A. Marshall, Mark N. Wu, Vadim Zipunnikov, John J. Kim, Jiawei Bai, Roy Yaari, Paul B. Rosenberg, Anton P. Porsteinsson, Cynthia M. Carlsson, Jiyoon Choi, Adam P. Spira, Sarah K. Wanigatunga, Jacobo Mintzer, Junrui Di, Reisa A. Sperling, and Rema Raman
Subjects: Oncology, medicine.medical_specialty, Amyloid, Disease, rhythm, Asymptomatic, cognitive, Internal medicine, wrist, medicine, Circadian rhythm, AcademicSubjects/MED00385, sleep, Morning, AcademicSubjects/SCI01870, business.industry, activity, Neurodegeneration, amyloid, Actigraphy, Original Articles, General Medicine, medicine.disease, Clinical trial, circadian, AcademicSubjects/MED00310, medicine.symptom, business, Alzheimer’s disease, AcademicSubjects/MED00370, actigraphy
Abstract: Study Objectives To examine in a subsample at the screening phase of a clinical trial of a β-amyloid (Aβ) antibody whether disturbed sleep and altered 24-hour rest/activity rhythms (RARs) may serve as markers of preclinical Alzheimer’s disease (AD). Methods Overall, 26 Aβ-positive (Aβ+) and 33 Aβ-negative (Aβ−) cognitively unimpaired participants (mean age = 71.3 ± 4.6 years, 59% women) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, respectively, wore actigraphs for 5.66 ± 0.88 24-hour periods. We computed standard sleep parameters, standard RAR metrics (mean estimating statistic of rhythm, amplitude, acrophase, interdaily stability, intradaily variability, relative amplitude), and performed a novel RAR analysis (function-on-scalar regression [FOSR]). Results We were unable to detect any differences between Aβ+ and Aβ− participants in standard sleep parameters or RAR metrics with our sample size. When we used novel FOSR methods, however, Aβ+ participants had lower activity levels than Aβ− participants in the late night through early morning (11:30 pm to 3:00 am), and higher levels in the early morning (4:30 am to 8:30 am) and from midday through late afternoon (12:30 pm to 5:30 pm; all p < .05). Aβ+ participants also had higher variability in activity across days from 9:30 pm to 1:00 am and 4:30 am to 8:30 am, and lower variability from 2:30 am to 3:30 am (all p < .05). Conclusions Although we found no association of preclinical AD with standard actigraphic sleep or RAR metrics, a novel data-driven analytic method identified temporally “local” RAR alterations in preclinical AD.
Published: 2021

27. Functional connectome vulnerability to Alzheimer’s disease in alcohol use disorder: A preliminary study

Author: Andrew B. Lawson, Jens H. Jensen, Andreana Benitez, Brandon Vaughan, Sudie E. Back, Duncan Nowling, Jane E. Joseph, Shaquanda Ross-Simmons, Graham Warner, Laura Lohnes, Jacobo Mintzer, Brian C. Dean, and Julianne C. Flanagan
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Vulnerability, Disease, Alcohol use disorder, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Functional connectome, Neurology (clinical), Geriatrics and Gerontology, business, Psychiatry
Published: 2020

28. Cannabinoids and Psychedelics for Neuropsychiatric Symptoms of Alzheimer's: Addressing Disparities Through Clinical Trials

Author: Brent Forester, Krista Lanctôt, Jacobo Mintzer, and Paul Rosenberg
Subjects: Psychiatry and Mental health, Geriatrics and Gerontology
Published: 2022

29. Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments

Author: Olga Brawman-Mintzer, Chris H. van Dyck, Nathan Herrmann, Jacobo Mintzer, William J. Burke, Abby Li, Suzanne Craft, Paul B. Rosenberg, Roberta W. Scherer, Alan J. Lerner, Prasad R. Padala, Anton P. Porsteinsson, Allan I. Levey, Krista L. Lanctôt, Danielle Vieira, and Hamadou Coulibaly
Subjects: Male, medicine.medical_specialty, Apathy, Context (language use), Disease, Article, Alzheimer Disease, Internal medicine, medicine, Dementia, Humans, In patient, Aged, business.industry, Methylphenidate, medicine.disease, Confidence interval, Clinical trial, Psychiatry and Mental health, Cross-Sectional Studies, Caregivers, Female, Geriatrics and Gerontology, medicine.symptom, business, medicine.drug
Abstract: Background Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. Objective The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. Methods ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. Results Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%–96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%–96.9%). Conclusion The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.
Published: 2020

30. Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate

Author: Nimra Jamil, Paul B. Rosenberg, Roberta W. Scherer, Olga Brawman-Mintzer, Jacobo Mintzer, Amy F.T. Arnsten, Krista L. Lanctôt, Alan J. Lerner, Christopher H. van Dyck, Anton P. Porsteinsson, Prasad R. Padala, Allan I. Levey, and Nathan Herrmann
Subjects: 030214 geriatrics, Methylphenidate, Apathy, Cognition, Disease, Degeneration (medical), 03 medical and health sciences, Psychiatry and Mental health, Norepinephrine, 0302 clinical medicine, Dopamine, Alzheimer Disease, medicine, Humans, Geriatrics and Gerontology, medicine.symptom, Psychology, Prefrontal cortex, Neuroscience, medicine.drug
Abstract: The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.
Published: 2020

31. Sex Differences in the Neuropsychiatric Symptoms of Patients With Alzheimer’s Disease

Author: David M. Shade, Ye Tao, Lea T. Drye, Cynthia A. Munro, Anton P. Porsteinsson, Constantine G. Lyketsos, Paul B. Rosenberg, Davangere P. Devanand, Lon S. Schneider, Daniel Weintraub, Jacobo Mintzer, Bruce G. Pollock, Jerome A. Yesavage, and Matthew E. Peters
Subjects: Male, medicine.medical_specialty, Behavioral Symptoms, Disease, Citalopram, Severity of Illness Index, Article, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Alzheimer Disease, Internal medicine, Multicenter trial, Activities of Daily Living, medicine, Humans, In patient, Psychomotor Agitation, Aged, Psychiatric Status Rating Scales, 030214 geriatrics, business.industry, General Neuroscience, Neuropsychiatric inventory, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Cross-Sectional Studies, Female, Geriatrics and Gerontology, Alzheimer's disease, business, Selective Serotonin Reuptake Inhibitors, 030217 neurology & neurosurgery, medicine.drug
Abstract: The aim of this study was to describe sex differences in neuropsychiatric symptoms (NPSs) in patients with Alzheimer’s disease (AD). Baseline scores on the Cohen-Mansfield Agitation Inventory, Neurobehavioral Rating Scale–Agitation subscale, and the Neuropsychiatric Inventory from patients with AD enrolled in a multicenter trial of citalopram for the treatment of agitation were analyzed. We found not only that patients with AD having agitation were likely to exhibit many other NPSs but also that the women in this study were more likely to exhibit a broader range of NPS than were the men. These results suggest greater heterogeneity in the clinical presentation of women compared to men, and thus in the potential targets for treatment in these patients. Further characterization of sex differences in NPS can inform future efforts aimed at establishing subtypes of patients for whom various treatment approaches will be most appropriate.
Published: 2018

32. Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease

Author: Jacobo, Mintzer, Krista L, Lanctôt, Roberta W, Scherer, Paul B, Rosenberg, Nathan, Herrmann, Christopher H, van Dyck, Prasad R, Padala, Olga, Brawman-Mintzer, Anton P, Porsteinsson, Alan J, Lerner, Suzanne, Craft, Allan I, Levey, William, Burke, Jamie, Perin, David, Shade, and Prakash, Babani
Subjects: Male, medicine.medical_specialty, Apathy, Placebo, law.invention, Randomized controlled trial, Alzheimer Disease, law, Internal medicine, medicine, Humans, Dementia, Aged, Aged, 80 and over, business.industry, Hazard ratio, Odds ratio, medicine.disease, Clinical trial, Methylphenidate, Clinical Global Impression, Central Nervous System Stimulants, Female, Neurology (clinical), medicine.symptom, business
Abstract: Importance Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality. Objective To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease. Design, Setting, and participants This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included. Interventions Ten milligrams of methylphenidate, twice daily, vs matching placebo. Main Outcomes and Measures The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life. Results Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, −1.25; 95% CI, −2.03 to −0.47;P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91;P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84;P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04;P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups. Conclusions and Relevance This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease. Trial Registration ClinicalTrials.gov Identifier:NCT02346201
Published: 2021

33. 102 - IPA Guidelines on Dementia and Agitation: From Provisional to Final

Author: Jacobo Mintzer, Paul A. Rosenberg, Jeffrey L. Cummings, Michael Splaine, and Mary Sano
Subjects: Psychiatry and Mental health, Clinical Psychology, medicine.medical_specialty, business.industry, Medicine, Dementia, Geriatrics and Gerontology, business, medicine.disease, Psychiatry, Gerontology
Abstract: Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. In 2015 IPA convened a transparent process to build a consensus definition of agitation and agreement on what elements should be included in the syndrome that resulted in publication of provisional guidelines. (Cummings et al, 2015) In the 2020-2021 year, the two co-chairs of this symposium have led a new workgroup to make the provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies and guide treatment final.Co-Chairs will discuss methods used in updating and findings and compare changes made to the provisional guidelines. Dr. Sano will present new findings on the biological basis of agitation in dementia and Dr. Mintzer will present on application of guidelines in the special circumstances of persons in palliative and hospice care. Dr. Rosenberg will discuss the special circumstance of agitation care in hospital emergency departments. Mr. Splaine will present findings about the utilization of the 2015 guidelines in the peer reviewed literature, professional and government dementia care guidance, and clinical trials.Cummings, J., Mintzer, J., Brodaty, H., Sano, M., Banerjee, S., Devanand, D., … Zhong, K. (2015). Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. International Psychogeriatrics, 27(1), 7-17. doi:10.1017/S1041610214001963
Published: 2021

34. Escitalopram for agitation in Alzheimer's disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial

Author: Cynthia A. Munro, Lillian Lourenco, Paul A. Rosenberg, Anne Shanklin Casper, Laurie M. Ryan, Constantine Frangakis, Constantine G. Lyketsos, Maurcio Becerra, Paul B. Rosenberg, Hochang Lee, Davangere P. Devanand, Liberty Teodoro, Stephan Ehrhardt, Asa Widman, Alvin D. McKelvy, Gregory Pelton Jacobo Mintzer, Milap A. Nowrangi, Dave Shade, Sonia Pawluczyk, Anton P. Porsteinsson, Anthony Awkar, Arthur Williams, Zahinoor Ismail, Benoit H. Mulsant, Andy Lears, Lon S. Schneider, Sarah Lawrence, Kyle Lago, Jamie Perin, Melanie Keltz, Laura Simon-Pearson, David M. Shade, Lea T. Drye, Jacobo Mintzer, Jennifer Jones, Olga Brawman-Mintzer, Nicholas Bienko, Devangere P. Devanand, Tarek K. Rajji, Sheriza N. Baksh, Karen S. Dagerman, Susan Salem-Spencer, Kim Martin, Nimra Jamil, Meghan Schultz, Sheriza Baksh, Kaitlyn Lane, Dimitri Avramopoulos, Sanjeev Kumar, Nancy Kowalski, and Bruce G. Pollock
Subjects: Male, medicine.medical_specialty, Epidemiology, Citalopram, Placebo, Article, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, Therapeutic approach, 0302 clinical medicine, Developmental Neuroscience, Randomized controlled trial, Double-Blind Method, law, Alzheimer Disease, Internal medicine, Medicine, Escitalopram, Dementia, Humans, 030212 general & internal medicine, Psychomotor Agitation, Aged, Aged, 80 and over, Psychiatric Status Rating Scales, business.industry, Health Policy, medicine.disease, 3. Good health, Clinical trial, Psychiatry and Mental health, Clinical Global Impression, Female, Neurology (clinical), Geriatrics and Gerontology, business, Psychosocial, 030217 neurology & neurosurgery, Selective Serotonin Reuptake Inhibitors, medicine.drug
Abstract: Introduction Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. Methods S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC). Discussion S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846).
Published: 2018

35. 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

36. Consensus provisional definition of agitation in cognitive disorders

Author: Cristina Sampaio, Henry Brodaty, David C. Steffens, Jacobo Mintzer, Mary Sano, Krista L. Lanctôt, Robert Howard, Serge Gauthier, Jeffrey Cummings, Elaine R. Peskind, Marc Wortmann, Anton P. Porsteinsson, Constantine G. Lyketsos, Devangere P. Devanand, Edgardo Reich, Sube Banerjee, and Kate Zhong
Subjects: Food and drug administration, medicine.medical_specialty, business.industry, Aggression, Epidemiology, Medicine, Cognition, medicine.symptom, business, Cognitive impairment, Clinical psychology
Published: 2019

37. Global Council on Brain Health: Consensus and Recommendations for Promoting Brain Health Through Music Engagement

Author: Jacobo Mintzer
Subjects: Abstracts, Health (social science), Life-span and Life-course Studies, AcademicSubjects/SOC02600, Health Professions (miscellaneous), human activities, behavioral disciplines and activities, humanities, Session 7170 (Symposium)
Abstract: This presentation will summarize the points of consensus reached by the experts and describes the major points of discussion that led to their recommendations for men and women age 50 and older. The GCBH considered questions surrounding what happens in the brain when listening to music as well as creating music. Topics such as music therapy and the clinical dimensions of introducing music into caring for patients will be addressed. Alongside the consensus points, recommendations and practical tips will be presented. Moreover, we will also identify gaps in our knowledge that currently exist in the evidence base surrounding music and brain health.
Published: 2020

38. Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer’s Disease

Author: Xiaoying Sun, Rema Raman, Anton P. Porsteinsson, Paul B. Rosenberg, Krista L. Lanctôt, Nathan Herrmann, and Jacobo Mintzer
Subjects: Male, medicine.medical_specialty, Apathy, Appetite, Motor Activity, Placebo, Neuropsychiatry, Severity of Illness Index, Dysphoria, 03 medical and health sciences, Cognition, 0302 clinical medicine, Alzheimer Disease, Internal medicine, mental disorders, medicine, Humans, 030212 general & internal medicine, Enzyme Inhibitors, Cognitive decline, Psychiatry, Adverse effect, Depression (differential diagnoses), Aged, Alanine, Dose-Response Relationship, Drug, Depression, business.industry, General Neuroscience, Repeated measures design, Azepines, General Medicine, Mental Status and Dementia Tests, Psychiatry and Mental health, Clinical Psychology, Female, Amyloid Precursor Protein Secretases, Geriatrics and Gerontology, medicine.symptom, Sleep, business, 030217 neurology & neurosurgery, Semagacestat, medicine.drug
Abstract: Background In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD). Objective We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). Methods 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline. Results Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased. Conclusion In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.
Published: 2016

39. Effects of Citalopram on Neuropsychiatric Symptoms in Alzheimer’s Dementia: Evidence From the CitAD Study

Author: Paul B. Rosenberg, Jeffery Newell, Jerome A. Yesavage, Jacobo Mintzer, Daniel Weintraub, Kelly M. Makino, D.P. Devanand, Constantine G. Lyketsos, David M. Shade, Bruce G. Pollock, Constantine Frangakis, Lon S. Schneider, Lea T. Drye, Matthew E. Peters, Cynthia A. Munro, Anton P. Porsteinsson, and Anne K. Leonpacher
Subjects: Male, Sleep Wake Disorders, medicine.medical_specialty, Hallucinations, Disease, Anxiety, Citalopram, Irritability, Placebo, behavioral disciplines and activities, Delusions, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Alzheimer Disease, law, Internal medicine, mental disorders, medicine, Humans, 030212 general & internal medicine, Psychiatry, Odds ratio, medicine.disease, Irritable Mood, Psychiatry and Mental health, Antidepressive Agents, Second-Generation, Female, medicine.symptom, Alzheimer's disease, Psychology, 030217 neurology & neurosurgery, medicine.drug
Abstract: Citalopram has been shown to improve agitation in patients with Alzheimer's disease. The authors evaluated whether other neuropsychiatric symptoms improve with citalopram treatment compared with placebo.In this planned secondary analysis of the Citalopram for Agitation in Alzheimer's Disease study, the authors evaluated the effect of citalopram on the 12 neuropsychiatric symptom domains assessed by the Neuropsychiatric Inventory (NPI). They compared caregiver-reported NPI scores at week 9 in patients receiving citalopram (30 mg/day) or placebo with regard to both the presence or absence of individual neuropsychiatric symptoms and individual domain scores (reflecting severity) in participants who had symptoms at week 9.At week 9, participants treated with citalopram were significantly less likely to be reported as showing delusions (odds ratio=0.40), anxiety (odds ratio=0.43), and irritability/lability (odds ratio=0.38). A comparison of median scores of participants with symptoms present at week 9 showed significant differences favoring citalopram for hallucinations and favoring placebo for sleep/nighttime behavior disorders.While dosage constraints must be considered because of citalopram's adverse effect profile, this agent's overall therapeutic effects in patients with Alzheimer's disease and agitation, in addition to efficacy for agitation/aggression, included reductions in the frequency of irritability, anxiety, and delusions; among patients who had these symptoms at week 9, they included a reduction in the severity of hallucinations but an increase in the severity of sleep/nighttime behavior disorders.
Published: 2016

40. Sedation mediates part of Citalopram's effect on agitation in Alzheimer's disease

Author: Leah Friedman, Cynthia A. Munro, Jerome A. Yesavage, Art Noda, Steven Z. Chao, Daniel Weintraub, Lea T. Drye, Jacobo Mintzer, Anton P. Porsteinsson, Devangere P. Devanand, Bruce G. Pollock, Michelle Madore, David M. Shade, Helena C. Kraemer, Lon S. Schneider, Paul B. Rosenberg, Jeffery Newell, Joy L. Taylor, and Constantine G. Lyketsos
Subjects: Psychomotor agitation, Sedation, Citalopram, Placebo, Article, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Alzheimer Disease, Rating scale, Outcome Assessment, Health Care, medicine, Humans, Hypnotics and Sedatives, Psychomotor Agitation, Biological Psychiatry, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Anesthesia, Alzheimer's disease, medicine.symptom, Psychology, Psychosocial, Selective Serotonin Reuptake Inhibitors, 030217 neurology & neurosurgery, Somnolence, medicine.drug
Abstract: Background We found a benefit of citalopram for agitation in the Citalopram for Agitation in Alzheimer's Disease study (CitAD), and wondered if this was mediated by a sedative effect. CitAD was a randomized, placebo-controlled, double-blind, parallel group trial conducted at 8 academic centers in the United States and Canada from August 2009 to January 2013. One hundred sixty-two participants with probable Alzheimer's disease (AD) and clinically significant agitation were analyzed in this study. Participants received a psychosocial intervention and were randomized to receive either citalopram or placebo (approximately half assigned to each group). Participants were rated on the Neurobehavioral Rating Scale Agitation subscale and measures of sedation (i.e., fatigue and somnolence). Methods Using the MacArthur Foundation procedures for documenting a mediator effect, we performed a secondary analysis examining whether sedation mediates the effect of treatment on agitation outcome. Results: We found a statistically significant mediating effect of sedation on agitation outcomes, but the magnitude of the effect was small, only explaining 11% of the variance in agitation, with a significant, but modest effect size of 0.16 (95% CI: 0.08 to 0.22). Conclusions The benefit of citalopram was partly due to sedation but largely due to other mechanisms of action.
Published: 2016

41. Psychometric Properties of Apathy Scales in Dementia: A Systematic Review

Author: Paul B. Rosenberg, Jacobo Mintzer, Courtney Ellis, Krista L. Lanctôt, Myuri Ruthirakuhan, Allison Rau, Dana Mohammad, and Nathan Herrmann
Subjects: Psychometrics, Population, Apathy, MEDLINE, Disease, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, Humans, education, education.field_of_study, 030214 geriatrics, business.industry, General Neuroscience, Reproducibility of Results, General Medicine, medicine.disease, Clinical trial, Psychiatry and Mental health, Clinical Psychology, Systematic review, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.
Published: 2018

42. Perspective from Clinical Research: Ethical Issues in Alzheimer's Disease Research

Author: Jacobo Mintzer
Subjects: 0301 basic medicine, Clinical Trials as Topic, Ethical issues, Health Policy, Perspective (graphical), MEDLINE, General Medicine, Disease, Coercion, Health Services Accessibility, Alzheimer's disease research, 03 medical and health sciences, Issues, ethics and legal aspects, 030104 developmental biology, 0302 clinical medicine, Clinical research, Alzheimer Disease, 030220 oncology & carcinogenesis, Humans, Engineering ethics, Psychology
Abstract: This paper attempts to bring to the attention of the readers a concept that broadens ethical considerations for Alzheimer's disease research. We propose we move away from the ethical paradigm that focuses on avoidance of coercion for participation in studies as well as privacy and safety to a more inclusive paradigm that will not only include the principles outlined above but will also guarantee access to new treatments for individuals that participate in research and other members of society. Specifically, if the research being performed results in a new treatment for Alzheimer's disease, would the individuals participating in the research and other members of their community have access to and benefit from these treatments, given the availability of financial and other resources in the society that will allow for the implementation of these treatments. This paper will propose a model that will facilitate the achievement of these broader ethical considerations.
Published: 2018

43. A retrospective, population-based cohort study of driving under the influence, Alzheimer's disease diagnosis, and survival

Author: Gelareh Rahimi, Margaret C. Miller, Dennis E. Orwat, and Jacobo Mintzer
Subjects: Male, medicine.medical_specialty, Pediatrics, Automobile Driving, Population, Alcohol abuse, Poison control, Alcohol use disorder, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Disease registry, Law Enforcement, Alzheimer Disease, Epidemiology, Medicine, Humans, Registries, education, Driving Under the Influence, Driving under the influence, Retrospective Studies, education.field_of_study, 030214 geriatrics, business.industry, celebrities, medicine.disease, United States, celebrities.reason_for_arrest, Psychiatry and Mental health, Clinical Psychology, Alcoholism, Diagnosis, Dual (Psychiatry), Female, Geriatrics and Gerontology, business, Gerontology, 030217 neurology & neurosurgery, Cohort study
Abstract: Introduction:The relationship between Alzheimer’s Disease (AD) and alcohol addiction is poorly characterized. Arrests for driving under the influence (DUI) can serve as a proxy for alcohol addiction. Therefore, the potential association between DUI and AD could be helpful in understanding the relationship between alcohol abuse and AD.Materials and methods:A retrospective, population-based cohort study using state health and law enforcement data was performed. The study cross-referenced 141,281 South Carolina Alzheimer’s Disease Registry cases with state law enforcement data.Results:Of the 2,882 registry cases (1.4%) found to have a history of at least one DUI arrest, cases were predominantly White (58.7%) and male (77.4%). Results showed a correlation coefficient of 0.7 (p < 0.0001) between the age of first DUI arrest and the age of AD diagnosis. A dose-response relationship between the number of DUIs and age of AD onset was found to exist, where those with a history of DUI arrest were diagnosed an average of 9.1 years earlier, with a further 1.8 years earlier age at diagnosis in those with two or more arrests for DUI. A history of DUI arrest was also found to be negatively associated with survival after diagnosis, with a 10% decreased life expectancy in those with a DUI arrest history.Conclusions:Driving under the influence, a potential indicator of alcohol addiction, is associated with an earlier onset of AD registry diagnosis and shortened survival after diagnosis. This study contributes to the growing body of evidence suggesting that some cases of AD are alcohol related and, possibly, postponable or preventable.
Published: 2018

44. P4‐280: BRAIN AMYLOID BURDEN, SLEEP, AND CIRCADIAN REST/ACTIVITY RHYTHMS: SCREENING FINDINGS FROM A4 AND LEARN

Author: Vadim Zipunnikov, Rema Raman, Roy Yaari, Anton P. Porsteinsson, Paul S. Aisen, Adam P. Spira, Caitlin Romano, Gad A. Marshall, Mark N. Wu, Jacobo Mintzer, Zeyun Lu, Sarah K. Wanigatunga, Reisa A. Sperling, Paul B. Rosenberg, and Cynthia M. Carlsson
Subjects: Epidemiology, business.industry, Health Policy, Rest activity, Sleep in non-human animals, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Rhythm, Developmental Neuroscience, Medicine, Amyloid burden, Neurology (clinical), Circadian rhythm, Geriatrics and Gerontology, business, Neuroscience
Published: 2018

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

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

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

Author: Jerome A. Yesavage, Thomas O. Obisesan, Ann Marie Hake, Yaakov Stern, Betty Lind, Daniel D'Agostino, Daniel Varon, Christine M. Belden, Evan Fletcher, Jef Williamson, Howard Feldman, Pauline Maillard, Stephanie Kielb, Dana Mathews, Henry Rusinek, Sonia Pawluczyk, Donna Munic, Michele Assaly, Ines Mahjoub, Barton Lane, Andrew J. Saykin, Raymundo Hernando, Randall Grifth, Paul S. Aisen, Brittany Cerbone, Saba Wolday, Douglas W. Scharre, Karen S. Anderson, Sara S. Mason, Marwan N. Sabbagh, Geofrey Tremont, Stacy Schneider, Marilyn S. Albert, Tracy Kendall, P. M. Doraiswamy, Antero Sarrael, Kenneth M. Spicer, George Bartzokis, Parianne Fatica, Christopher H. van Dyck, Maria Carroll, Benita Mudge, Beau M. Ances, Brandy R. Matthews, Allyson C. Rosen, Chiadi U. Onyike, Gloria Chaing, Helen Vanderswag, Javier Villanueva-Meyer, Stephanie Reeder, Erin E. Franklin, Sandra Weintraub, Liberty Teodoro, Connie Brand, Arthur W. Toga, Mony J. de Leon, Sandra E. Black, Robert C. Green, Russell H. Swerdlow, Leyla deToledo-Morrell, Bryan M. Spann, Judith L. Heidebrink, Leslie Shaw, Ruth A. Mulnard, Rob Bartha, Sterling C. Johnson, Kristin Fargher, Susan De Santi, Curtis Caldwell, Rachelle S. Doody, Erik D. Roberson, Norman R. Relkin, Kathleen Johnson, Raj C. Shah, Kris Johnson, Diana Kerwin, M.-Marsel Mesulam, Howard J. Rosen, Peggy Roberts, Michael Borrie, Martin R. Farlow, Steven G. Potkin, Reisa A. Sperling, John Q. Trojanowki, Amanda Smith, James J. Lah, Mary L. Creech, Janet S. Cellar, Michael Lin, Terence Z. Wong, Howard Bergman, Dana M. Pogorelec, Gaby Thai, Jacobo Mintzer, Raina Carter, Heather Johnson, Francine Parftt, Karen Blank, Daniel C. Marson, Nancy Johnson, Susan Rountree, Michelle Rainka, Elizabeth Oates, Stephen Correia, John C. Morris, Alan J. Lerner, Pradeep Garg, Mauricio Beccera, Mary L. Hynes, Chuang Kuo Wu, Curtis Tatsuoka, Brian R. Ott, Joy L. Taylor, Mohamed Ali Mahjoub, Adrian Preda, Islem Rekik, Ronald C. Petersen, Kathleen Tingus, Vernice Bates, Irina Rachisky, Neill Graf-Radford, Alexander Norbash, Teresa Villena, Paul Malloy, Cliford Jack, Pierre N. Tariot, Anton P. Porsteinsson, Jefrey Burns, Owen Carmichael, Maria T. Greig, Marc Seltzer, Pradeep Varma, Jefrey Petrella, James E. Galvin, Joseph F. Quinn, Franklin Watkins, John M Olichney, Joanne L. Lord, Raymond Scott Turner, Adam S. Fleisher, Salvador Borges-Neto, James B. Brewer, Carl H. Sadowsky, Andrew E. Budson, Martha G. MacAvoy, Joanne S. Allard, L. Schneider, Stephen Salloway, Kim Martin, Mary Quiceno, Kaycee M. Sink, Sanjay Asthana, Laurel A. Beckett, Alice D. Brown, David S. Knopman, Neil W. Kowall, Efe Mitsis, Elizabeth Finger, David C. Perry, Bojana Stefanovic, David S. Geldmacher, Andrew Kertesz, Cynthia M. Carlsson, Charles Bernick, Earl A. Zimmerman, Bonnie S. Goldstein, Dzintra Celmins, Paula Ogrocki, Daniel H.S. Silverman, David G. Clark, Charles D. Smith, Nunzio Pomara, Stephen Pasternack, Howard Chertkow, Christina A. Michel, Sandra W. Jacobson, Po Lu, Peter A. Hardy, Greg Jicha, David Bachman, Laura A. Flashman, Munir Chowdhury, Bruce L. Miller, Ging Yuek Robin Hsiung, Horacio Capote, Gad A. Marshall, Brigid Reynolds, Jefrey Kaye, Patricia Lynn Johnson, Ronald J. Killiany, Mimi Dang, Smita Kittur, Lawrence S. Honig, Ranjan Duara, T. Y. Lee, Keith A. Johnson, Karen L. Bell, Allan I. Levey, Scott Herring, Michael W. Weiner, Ellen Woo, Dana Nguyen, Robert B. Santulli, Godfrey D. Pearlson, Mark A. Mintun, Sara Dolen, Jared R. Tinklenberg, Edward Coleman, Jared R. Brosch, John C. Brockington, William Brooks, Partha Sinha, M. Ismail, Balebail Ashok Raj, Lisa D. Ravdin, Kristine Lipowski, Charles DeCarli, Borna Bonakdarpour, Colleen S. Albers, Chris Hosein, Marissa Natelson Love, Kyle B. Womack, Maria Kataki, Nadira Trncic, Anna Burke, Sherye A. Sirrel, Henry W. Querfurth, Liana G. Apostolova, Angela Oliver, William J. Jagust, Richard E. Carson, Cynthia Hunt, Lidia Glodzik, Hillel Grossman, Gary R. Conrad, Leslie Gordineer, Catherine Mc-Adams-Ortiz, Dick Trost, Kelly M. Makino, Anahita Adeli, and Lisa C. Silbert
Subjects: Right entorhinal cortex, Models, Neurological, lcsh:Medicine, Biology, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, Middle frontal gyrus, Dementia, Patient treatment, lcsh:Science, Cognitive impairment, Multidisciplinary, Extramural, lcsh:R, Brain, Diagnostic marker, Alzheimer’s Disease Neuroimaging Initiative, medicine.disease, Magnetic Resonance Imaging, Brain region, lcsh:Q, Cognition Disorders, Neuroscience, Biomarkers, 030217 neurology & neurosurgery
Abstract: Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer’s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, ‘shape connections’ between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus.
Published: 2018

47. Change in agitation in Alzheimer's disease in the placebo arm of a nine-week controlled trial

Author: Jeffery Newell, Paul B. Rosenberg, Jacobo Mintzer, Christopher Marano, Daniel Weintraub, Constantine G. Lyketsos, Bruce G. Pollock, Constantine Frangakis, Curtis L. Meinert, David M. Shade, Cynthia A. Munro, Gregory H. Pelton, Anton P. Porsteinsson, Lon S. Schneider, Jerome A. Yesavage, Devangere P. Devanand, Zahinoor Ismail, Peter V. Rabins, and Lea T. Drye
Subjects: Male, medicine.medical_specialty, Activities of daily living, Psychomotor agitation, Citalopram, Placebo, Severity of Illness Index, Article, law.invention, Double-Blind Method, Randomized controlled trial, Alzheimer Disease, law, Rating scale, Regression toward the mean, Activities of Daily Living, Severity of illness, medicine, Humans, Psychiatry, Psychomotor Agitation, Aged, Aged, 80 and over, Psychiatric Status Rating Scales, Placebo Effect, Aggression, Clinical trial, Psychiatry and Mental health, Clinical Psychology, Treatment Outcome, Caregivers, Physical therapy, Antidepressive Agents, Second-Generation, Female, Geriatrics and Gerontology, medicine.symptom, Psychology, Gerontology
Abstract: Background:Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD).Methods:In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.Results:Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.Conclusions:We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
Published: 2015

48. Citalopram for the Treatment of Agitation in Alzheimer Dementia

Author: Vijay Vaidya, Bruce G. Pollock, Paul B. Rosenberg, Davangere P. Devanand, Lea T. Drye, David M. Shade, Lon S. Schneider, Daniel Weintraub, Jerome A. Yesavage, Anton P. Porsteinsson, Jacobo Mintzer, Matthew E. Peters, Constantine G. Lyketsos, and Dimitri Avramopoulos
Subjects: Male, Apolipoprotein E, Databases, Factual, Genotype, Psychomotor agitation, Citalopram, Pharmacology, Article, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, Double-Blind Method, Alzheimer Disease, medicine, Humans, Dementia, Serotonin Uptake Inhibitors, Psychomotor Agitation, Serotonin transporter, Aged, Aged, 80 and over, Serotonin Plasma Membrane Transport Proteins, 030214 geriatrics, biology, Brain-Derived Neurotrophic Factor, medicine.disease, Antidepressive Agents, Cytochrome P-450 CYP2C19, Psychiatry and Mental health, Treatment Outcome, Caregivers, Receptors, Serotonin, Anesthesia, biology.protein, Antidepressant, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, Alzheimer's disease, Psychology, Selective Serotonin Reuptake Inhibitors, 030217 neurology & neurosurgery, medicine.drug
Abstract: Objective: To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A ( HTR2A-T102C), serotonin receptor 2C ( HTR2C-Cys23Ser), serotonin transporter ( 5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 ( CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study—Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory. Method: We utilized data from the Citalopram for Agitation in Alzheimer’s Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures. Results: Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks. Discussion: Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation.
Published: 2015

49. [O1–01–06]: MEASURING APATHY IN ALZHEIMER'S DISEASE IN THE APATHY IN DEMENTIA METHYLPHENIDATE TRIAL 2 (ADMET 2): A COMPARISON OF INSTRUMENTS

Author: Olga Brawman-Mintzer, William J. Burke, Christopher H. van Dyck, Anton P. Porsteinsson, Jacobo Mintzer, Paul B. Rosenberg, Alan J. Lerner, Suzanne Craft, Prasad R. Padala, Krista L. Lanctôt, Roberta W. Scherer, Allan I. Levey, Nathan Herrmann, and Abby Li
Subjects: medicine.medical_specialty, Epidemiology, Methylphenidate, Health Policy, Disease, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Dementia, Apathy, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, Psychology, Psychiatry, medicine.drug
Published: 2017

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

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

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