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

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, 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, 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, Robert C. Green, Tom Montine, Ronald Petersen, Paul Aisen, Gustavo Jimenez, Michael Donohue, Devon Gessert, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimer, Laurel Beckett, Danielle Harvey, Michael Donohue, Clifford R. Jack, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, William Jagust, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Leslie M. Shaw, John Q. Trojanowki, Virginia Lee, Magdalena Korecka, Michal Figurski, Arthur W. Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Michael W. Weiner, Lean Thal, Zaven Khachaturian, Leon Thal, Neil Buckholtz, Michael W. Weiner, Peter J. Snyder, William Potter, Steven Paul, Marilyn Albert, Richard Frank, Zaven Khachaturian, 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, Ronald Petersen, 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, John C. Morris, 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, Marilyn Albert, 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 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, Adam Fleisher, 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, Elizabeth Finger, Stephen Pasternak, Irina Rachinsky, John Rogers, Andrew Kertesz, Dick Drost, 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, Michael W. Weiner, Paul Aisen, Michael Weiner, Paul Aisen, Ronald Petersen, Robert C. Green, Danielle Harvey, Clifford R. Jack, William Jagust, John C. Morris, Andrew J. Saykin, Leslie M. Shaw, Arthur W. Toga, John Q. Trojanowki, Thomas Neylan, Jordan Grafman, Robert C. Green, Tom Montine, Michael Weiner, Ronald Petersen, Paul Aisen, Gustavo Jimenez, Michael Donohue, Devon Gessert, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimen, Thomas Neylan, Jacqueline Hayes, Shannon Finley, Danielle Harvey, Michael Donohue, Clifford R. Jack, Matthew Bernstein, Bret Borowski, Jeff Gunter, Matt Senjem, Kejal Kantarci, Chad Ward, William Jagust, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Householder, Leslie M. Shaw, John Q. Trojanowki, Virginia Lee, Magdalena Korecka, Michal Figurski, Arthur W. Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Michael W. Weiner, Karl Friedl, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, James Brewer, Helen Vanderswag, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Debra Fleischman, Konstantinos Arfanakis, Raj C. Shah, Ranjan Duara, Daniel Varon, Maria T Greig, P. Murali Doraiswamy, Jeffrey R. Petrella, Olga James, Anton P. Porsteinsson, Bonnie Goldstein, Kimberly S. Martin, Steven G. Potkin, Adrian Preda, Dana Nguyen, Jacobo Mintzer, Dino Massoglia, Olga Brawman-Mintzer, Carl Sadowsky, Walter Martinez, Teresa Villena, William Jagust, Susan Landau, Howard Rosen, David Perry, Raymond Scott Turner, Kelly Behan, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Marwan N. Sabbagh, Sandra A. Jacobson, Sherye A. Sirrel, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Joy L. Taylor, Ansgar J. Furst, Steven Chao, Norman Relkin, Gloria Chiang, Lisa Ravdin, Scott Mackin, Paul Aisen, Rema Raman, Scott Mackin, Michael Weiner, Paul Aisen, Rema Raman, Clifford R. Jack, Susan Landau, Andrew J. Saykin, Arthur W. Toga, Charles DeCarli, Robert A. Koeppe, Robert C. Green, Erin Drake, Michael Weiner, Paul Aisen, Rema Raman, Mike Donohue, Gustavo Jimenez, Devon Gessert, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimer, Elizabeth Shaffer, Scott Mackin, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Clifford R. Jack, Matthew Bernstein, Bret Borowski, Jeff Gunter, Matt Senjem, Kejal Kantarci, Chad Ward, Denise Reyes, Robert A. Koeppe, Susan Landau, Arthur W. Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Tatiana M. Foroud, Kelley M. Faber, Kwangsik Nho, Kelly N. Nudelman, Scott Mackin, Howard Rosen, Craig Nelson, David Bickford, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, Dariella Fernandez, Meryl Butters, Michelle Zmuda, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson

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.