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1. 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

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

Author

Howard Feldman, Anton P. Porsteinsson, Lon S. Schneider, Eben S. Schwartz, Earl A. Zimmerman, Richard V. King, Nunzio Pomara, James E. Galvin, M. Marcel Mesulam, Paula Ogrocki, Howard Chertkow, Gail Li, Gad A. Marshall, Kewei Chen, Norbert Schuff, Magdalena Korecka, MaryAnn Oakley, Elaine R. Peskind, Stephen Salloway, Kristine Lipowski, Clifford R. Jack, Charles DeCarli, Greg Jicha, Kathleen Tingus, Tatiana Foroud, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Sonia Pawluczyk, Mary Quiceno, Kaycee M. Sink, Paul S. Aisen, Peter Davies, Chris Hosein, Erin Householder, Adam Schwartz, Munir Chowdhury, Bruce L. Miller, James J. Lah, Steven E. Arnold, Kenneth M. Spicer, Keith A. Johnson, Karen L. Bell, Laura L. Boles Ponto, Olga James, Stephanie Reeder, Catherine Mc-Adams-Ortiz, Michele Assaly, Melissa J. Davis, Zaven Khachaturian, Leon J. Thal, Allan I. Levey, Betty Lind, Michael D. Devous, P. Murali Doraiswamy, John Q. Trojanowki, Jason Karlawish, Karen S. Anderson, Kejal Kantarci, Raina Carter, Gaby Thai, Tracy Kendall, Bojana Stefanovic, George Bartzokis, M.S. Albert, Donna Munic, Kelly M. Makino, Anahita Adeli, Franz Hefti, Dzintra Celmins, Marwan N. Sabbagh, Nigel J. Cairns, John C. Morris, Donna M. Simpson, Brandy R. Matthews, Marilyn S. Albert, Sterling C. Johnson, Curtis B. Caldwell, Greg Sorensen, Geoffrey Tremont, Charles Bernick, Susan De Santi, Jeffrey R. Petrella, Scott C. Neu, Jeffrey Kaye, Randall Griffith, Helen Vanderswag, Mauricio Beccera, M. L. Senjem, Charles D. Smith, David S. Knopman, Lisa Taylor-Reinwald, Chet Mathis, Susan M. Landau, Dana Nguyen, Nick C. Fox, Adrian Preda, Robert A. Koeppe, Cynthia Hunt, Benita Mudge, Lisa Raudin, Dick J. Drost, Steven M. Paul, Heather Anderson, Michal J. Figurski, Davie Holtzman, Scott Herring, Robert B. Santulli, Chad Ward, Godfrey D. Pearlson, Mark A. Mintun, Joseph F. Quinn, Thomas C. Neylan, M. Saleem Ismail, Alan J. Lerner, Sherye A. Sirrel, Henry W. Querfurth, Rosemary H Morrison, Ronald G. Thomas, Peter A. Hardy, Bryan M. Spann, Kristen Martin-Cook, Robert C. Green, John M Olichney, Lidia Glodzik, Pradeep Garg, Oscar L. Lopez, Annmarie Hake, Douglas W. Scharre, Raymond Scott Turner, Michael Borrie, Sara Dolen, Marc Raichle, Leyla de Toledo-Morrell, Jeffrey M. Burns, Joy L. Taylor, Balebail Ashok Raj, Irina Rachinsky, David Bachman, Horacio Capote, Erik D. Roberson, Effie M. Mitsis, Richard Frank, Michael W. Weiner, Michael C. Donohue, Ansgar J. Furst, Adam S. Fleisher, David S. Geldmacher, Joanne S. Allard, Gus Jiminez, Jared R. Tinklenberg, Teresa Villena, Ranjan Duara, Elizabether Finger, T. Y. Lee, Sanjay Asthana, Dino Massoglia, Alice D. Brown, Neil W. Kowall, Kim Martin, Angela Oliver, Ellen Woo, Susan Rountree, Peggy Roberts, Terence Z. Wong, Meghan Frey, Sandra Harding, Virginia M.-Y. Lee, Taylor W. Schmitz, William J. Jagust, Daniel Varon, Michelle Rainka, Norm Foster, Matt A. Bernstein, Colleen S. Albers, Elizabeth Oates, Myron F. Weiner, Eric C. Petrie, Andrew Kertesz, Janet S. Cellar, Karen Crawford, Christine M. Belden, Chuang-Kuo Wu, Jordan Grafman, Walter Martinez, Devon Gessert, John C. Brockington, David J. Clark, David A. Wolk, Heather E. Johnson, Alexander Norbash, Hillel Grossman, Gary R. Conrad, Kelley Faber, Jacqueline Hayes, Sandra Jacobson, Diana R. Kerwin, Franklin Watkins, T. J. Montine, Ramon Diaz-Arrastia, Hyungsub Shim, Leon Hudson, Jeff Gunter, Partha Sinha, Peter J. Snyder, Norman R. Relkin, Ruth A. Mulnard, Francine Parfitt, David Jones, Nancy Collins Johnson, Tamie Sather, Evan Fletcher, Sarah Walter, Jerome A. Yesavage, Antero Sarrael, Sungeun Kim, Brigid Reynolds, Maria T. Greig, Patricia Lynn Johnson, Stacy Schneider, Yaakov Stern, Beau M. Ances, Steven G. Potkin, Ronald J. Killiany, Mimi Dang, Smita Kittur, James B. Brewer, Chiadi U. Onyike, Paul M. Thompson, Mony J. de Leon, Sandra E. Black, Lawrence S. Honig, Rob Bartha, Gloria Chaing, R. Nathan Spreng, Rachelle S. Doody, Shannon Finley, Stephen H. Pasternak, Brian R. Ott, Reisa A. Sperling, Tamar J. Kitzmiller, John K. Hsiao, Kwangsik Nho, Richard E. Carson, Howard Bergman, Cynthia M. Carlsson, Bonnie S. Goldstein, Kyle B. Womack, Maria Kataki, Lew Kuller, Liana G. Apostolova, J. Jay Fruehling, Daniel D'Agostino, Christina A. Michel, Susan K. Schultz, Howard Fillit, Konstantinos Arfanakis, John A. Rogers, Dana Mathews, Ging-Yuek Robin Hsiung, Barton Lane, Brittany Cerbone, Sara S. Mason, Stephanie Kielb, Kris A. Johnson, Henry Rusinek, Liberty Teodoro, Connie Brand, Jeff D. Williamson, Prashanthi Vemuri, Russell H. Swerdlow, Judith L. Heidebrink, Paul Malloy, Pierre N. Tariot, Bret J. Borowski, Karl E. Friedl, Debra A. Fleischman, Martin R. Farlow, Javier Villanueva-Meyer, Eric M. Reiman, Jacobo Mintzer, Stephen Correia, Po H. Lu, Daniel C. Marson, Steven Potkin, Vernice Bates, Li Shen, Kathleen R. Johnson, Allyson C. Rosen, Neil Buckholtz, Andrew J. Saykin, Raymundo Hernando, Raj C. Shah, M.-Marsel Mesulam, Christopher H. van Dyck, Maria Carroll, Howard J. Rosen, Karen E. Smith, Arthur W. Toga, Leslie M. Shaw, Kristin Fargher, Karen Blank, Ronald C. Petersen, Amanda Smith, Owen Carmichael, Laurel A. Beckett, Sue Leon, William Z. Potter, Neill R. Graff-Radford, Danielle J Harvey, Joanne L. Lord, and Carl H. Sadowsky

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, Amyloid, Basal Forebrain, Science, General Physics and Astronomy, Degeneration (medical), Grey matter, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Entorhinal Cortex, Humans, Aged, Aged, 80 and over, Basal forebrain, Multidisciplinary, Amyloid beta-Peptides, business.industry, General Chemistry, medicine.disease, Entorhinal cortex, Prognosis, Magnetic Resonance Imaging, 030104 developmental biology, medicine.anatomical_structure, Biomarker (medicine), Female, Alzheimer's disease, business, 030217 neurology & neurosurgery, Biomarkers, Alzheimer's Disease Neuroimaging Initiative
Abstract

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Published
2016

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

Author

Sandra Harding, Allyson Rosen, Paul Malloy, Anton P. Porsteinsson, Ramon Diaz-Arrastia, Richard V. King, James E. Galvin, Ruth A. Mulnard, Maria T. Greig, Nunzio Pomara, James B. Brewer, Gus Jiminez, Susan De Santi, Pierre N. Tariot, Bret J. Borowski, Dick J. Drost, Howard Chertkow, Gail Li, Eric C. Petrie, Amanda Smith, Steven G. Potkin, Stephen Salloway, Jared R. Tinklenberg, Jacqueline Hayes, John C. Brockington, Robert B. Santulli, John K. Hsiao, Kwangsik Nho, Mary Quiceno, Kaycee M. Sink, Richard E. Carson, Keith A. Johnson, Daniel Varon, Michal J. Figurski, Christine M. Belden, Godfrey D. Pearlson, Mark A. Mintun, Elaine R. Peskind, Shannon Finley, Howard Bergman, Charles D. Smith, Helen Vanderswag, David Glenn Clark, Michael Borrie, Peggy Roberts, Terence Z. Wong, David S. Knopman, Michelle Rainka, Greg Jicha, Tamar J. Kitzmiller, Michael C. Donohue, Davie Holtzman, Hyungsub Shim, Gaby Thai, Bojana Stefanovic, Cynthia M. Carlsson, Elizabeth Oates, Kelley Faber, Kristen Martin-Cook, John M Olichney, Bonnie S. Goldstein, Robert C. Green, Kyle B. Womack, Maria Kataki, Robert A. Koeppe, Alexander Norbash, Sonia Pawluczyk, Neil Buckholtz, Chet Mathis, Betty Lind, Michael D. Devous, Leon J. Thal, Allan I. Levey, Munir Chowdhury, Bruce L. Miller, P. Murali Doraiswamy, Sanjay Asthana, Dino Massoglia, Alice D. Brown, Donna Munic, J. Jay Fruehling, Angela Oliver, Paul S. Aisen, Adam Schwartz, Antero Sarrael, Christina A. Michel, Susan K. Schultz, Thomas C. Neylan, Kenneth M. Spicer, Scott Herring, Jeff Gunter, Daniel D'Agostino, Neil W. Kowall, Karen L. Bell, José María Mateos-Pérez, MaryAnn Oakley, Richard Frank, Beau M. Ances, Lew Kuller, Liana G. Apostolova, Marwan N. Sabbagh, Sterling C. Johnson, Charles Bernick, Scott C. Neu, Susan M. Landau, William J. Jagust, Dana Nguyen, Olga James, Stephanie Reeder, David Bachman, Karl E. Friedl, John Rogers, Karen Crawford, Debra A. Fleischman, Martin R. Farlow, Javier Villanueva-Meyer, Raj C. Shah, Jeffrey Kaye, Randall Griffith, Laura L. Boles Ponto, Ellen Woo, Michele Assaly, Cynthia Hunt, Andrew Kertesz, Lidia Glodzik, Ansgar J. Furst, Eric M. Reiman, Jacobo Mintzer, Mony J. de Leon, Chiadi U. Onyike, Paul M. Thompson, Gloria Chaing, David S. Geldmacher, Tamie Sather, Evan Fletcher, M.-Marsel Mesulam, Howard J. Rosen, Lawrence S. Honig, Stephen Correia, Steven Potkin, Howard Feldman, Greg Sorensen, Yaakov Stern, Karen Elizabeth Smith, Norm Foster, Matt A. Bernstein, Meghan Frey, Roberto C. Sotero, Sandra E. Black, Tatiana Foroud, Janet S. Cellar, David A. Wolk, Sarah Walter, Oscar L. Lopez, Nick C. Fox, Po H. Lu, Daniel C. Marson, Li Shen, Heather Johnson, Joy L. Taylor, Heather Anderson, Yasser Iturria-Medina, George Bartzokis, M.S. Albert, Brigid Reynolds, Geoffrey Tremont, Patricia Lynn Johnson, Earl A. Zimmerman, Sara Dolen, Virginia M.-Y. Lee, Stacy Schneider, Kris Johnson, Irina Rachinsky, Reisa A. Sperling, Walter Martinez, Vernice Bates, John Q. Trojanowki, David T.W. Jones, Chuang Kuo Wu, Michael W. Weiner, Brandy R. Matthews, Peter J. Snyder, James J. Lah, Raina Carter, Franz Hefti, Hillel Grossman, Gary R. Conrad, Norman R. Relkin, Steven M. Paul, Ronald J. Killiany, Mimi Dang, Francine Parfitt, Franklin Watkins, T. J. Montine, Teresa Villena, Ranjan Duara, Smita Kittur, Paula Ogrocki, Andrew J. Saykin, Raymundo Hernando, Paule-Joanne Toussaint, John C. Morris, Elizabether Finger, T. Y. Lee, Donna M. Simpson, Stephen H. Pasternak, Kewei Chen, Rob Bartha, Dzintra Celmins, Chad Ward, Zaven S. Khachaturian, Brian R. Ott, M. Marcel Mesulam, Lisa Taylor-Reinwald, Magdalena Korecka, Lon S. Schneider, Eben S. Schwartz, Liberty Teodoro, Rachelle S. Doody, Myron F. Weiner, Jerome A. Yesavage, Peter A. Hardy, M. Saleem Ismail, Connie Brand, Alan J. Lerner, Gad A. Marshall, Clifford R. Jack, Ronald C. Petersen, Pradeep Garg, Alan C. Evans, Russell H. Swerdlow, Bryan M. Spann, Horacio Capote, Karen E. Anderson, Adrian Preda, Judith L. Heidebrink, Sandra Jacobson, Catherine Mc-Adams-Ortiz, Marc Raichle, Owen Carmichael, Joseph F. Quinn, Adam S. Fleisher, Curtis Caldwell, Joanne S. Allard, Ronald G. Thomas, Kathleen Tingus, Barton Lane, Sue Leon, Raymond Scott Turner, Leyla de Toledo-Morrell, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Annmarie Hake, Peter Davies, Nigel J. Cairns, Kelly M. Makino, Jason Karlawish, Douglas W. Scharre, Nancy Johnson, Anahita Adeli, Diana R. Kerwin, Leon Hudson, Mauricio Beccera, M. L. Senjem, Sherye A. Sirrel, Henry W. Querfurth, Rosemary H Morrison, Tracy Kendall, Neill R. Graff-Radford, Danielle J Harvey, Joanne L. Lord, Carl H. Sadowsky, Kim Martin, Laurel A. Beckett, William Z. Potter, Christopher H. van Dyck, Maria Carroll, Arthur W. Toga, Leslie M. Shaw, Kristin Fargher, Melissa Davis, Karen Blank, Benita Mudge, Erik D. Roberson, Effie M. Mitsis, Kathleen Johnson, Partha Sinha, Sungeun Kim, Colleen S. Albers, Jordan Grafman, Devon Gessert, Kristine Lipowski, Charles DeCarli, Chris Hosein, Erin Householder, Steven E. Arnold, Kejal Kantarci, Marilyn S. Albert, Jeffrey R. Petrella, Lisa Raudin, Norbert Schuff, Jeffrey M. Burns, Balebail Ashok Raj, Susan Rountree, Dana Mathews, Ging-Yuek Robin Hsiung, Brittany Cerbone, Sara S. Mason, Howard Fillit, Konstantinos Arfanakis, Stephanie Kielb, Henry Rusinek, Jeff D. Williamson, and Prashanthi Vemuri

Subjects
0301 basic medicine, Male, Aging, General Physics and Astronomy, Disease, Neurodegenerative, Alzheimer's Disease, Brain mapping, Diagnostic Radiology, Computer-Assisted, 0302 clinical medicine, Models, 2.1 Biological and endogenous factors, Alzheimer's Disease including Alzheimer's Disease Related Dementias, Aetiology, Cognitive decline, Brain Mapping, Multidisciplinary, Brain, Cognition, Blood Proteins, Statistical, Middle Aged, Magnetic Resonance Imaging, Cerebrovascular Circulation, Neurological, Disease Progression, Biomedical Imaging, Female, Alzheimer's disease, Alzheimer's Disease Neuroimaging Initiative, Science, Neuroimaging, tau Proteins, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Alzheimer Disease, Image Interpretation, Computer-Assisted, Acquired Cognitive Impairment, medicine, Humans, Cognitive Dysfunction, Image Interpretation, Pathological, Aged, Amyloid beta-Peptides, Models, Statistical, business.industry, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer’s Disease Neuroimaging Initiative, General Chemistry, medicine.disease, Brain Disorders, 030104 developmental biology, Glucose, Positron-Emission Tomography, Multivariate Analysis, Dementia, business, Neuroscience, 030217 neurology & neurosurgery, Biomarkers
Abstract

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Published
2015
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