@ARTICLE{10.3389/fnagi.2019.00208, AUTHOR={Li, Yuan and Yao, Zhijun and Yu, Yue and Fu, Yu and Zou, Ying and Hu, Bin and , for the Alzheimer’s Disease Neuroimaging Initiative and Weiner, Michael W. and Aisen, Paul and Weiner, Michael and Aisen, Paul and Petersen, Ronald and Jack, Clifford R. and Jagust, William and Trojanowki, John Q. and Toga, Arthur W. and Beckett, Laurel and Green, Robert C. and Saykin, Andrew J. and Morris, John and Shaw, Leslie M. and Khachaturian, Zaven and Sorensen, Greg and Carrillo, Maria and Kuller, Lew and Raichle, Marc and Paul, Steven and Davies, Peter and Fillit, Howard and Hefti, Franz and Holtzman, David and Mesulam, M. Marcel and Potter, William and Snyder, Peter and Green, Robert C. and Montine, Tom and Petersen, Ronald and Aisen, Paul and Jimenez, Gustavo and Donohue, Michael and Gessert, Devon and Harless, Kelly and Salazar, Jennifer and Cabrera, Yuliana and Walter, Sarah and Hergesheimer, Lindsey and Beckett, Laurel and Harvey, Danielle and Donohue, Michael and Jack, Clifford R. and Bernstein, Matthew and Fox, Nick and Thompson, Paul and Schuff, Norbert and DeCArli, Charles and Borowski, Bret and Gunter, Jeff and Senjem, Matt and Vemuri, Prashanthi and Jones, David and Kantarci, Kejal and Ward, Chad and Jagust, William and Koeppe, Robert A. and Foster, Norm and Reiman, Eric M. and Chen, Kewei and Mathis, Chet and Morris, John C. and Cairns, Nigel J. and Franklin, Erin and Taylor-Reinwald, Lisa and Shaw, Leslie M. and Trojanowki, John Q. and Lee, Virginia and Korecka, Magdalena and Figurski, Michal and Toga, Arthur W. and Crawford, Karen and Neu, Scott and Saykin, Andrew J. and Foroud, Tatiana M. and Potkin, Steven and Shen, Li and Faber, Kelley and Kim, Sungeun and Nho, Kwangsik and Weiner, Michael W. and Thal, Lean and Khachaturian, Zaven and Thal, Leon and Buckholtz, Neil and Weiner, Michael W. and Snyder, Peter J. and Potter, William and Paul, Steven and Albert, Marilyn and Frank, Richard and Khachaturian, Zaven and Hsiao, John and Quinn, Joseph and Silbert, Lisa C. and Lind, Betty and Kaye, Jeffrey A. and Carter, Raina and Dolen, Sara and Schneider, Lon S. and Pawluczyk, Sonia and Becerra, Mauricio and Teodoro, Liberty and Spann, Bryan M. and Brewer, James and Vanderswag, Helen and Fleisher, Adam and Ziolkowski, Jaimie and Heidebrink, Judith L. and Lord, Joanne L. and Petersen, Ronald and Mason, Sara S. and Albers, Colleen S. and Knopman, David and Johnson, Kris and Villanueva-Meyer, Javier and Pavlik, Valory and Pacini, Nathaniel and Lamb, Ashley and Kass, Joseph S. and Doody, Rachelle S. and Shibley, Victoria and Chowdhury, Munir and Rountree, Susan and Dang, Mimi and Stern, Yaakov and Honig, Lawrence S. and Bell, Karen L. and Yeh, Randy and Ances, Beau and Morris, John C. and Winkfield, David and Carroll, Maria and Oliver, Angela and Creech, Mary L. and Mintun, Mark A. and Schneider, Stacy and Marson, Daniel and Geldmacher, David and Love, Marissa Natelson and Griffith, Randall and Clark, David and Brockington, John and Grossman, Hillel and Mitsis, Effie and Shah, Raj C. and Lamar, Melissa and Samuels, Patricia and Duara, Ranjan and Greig-Custo, Maria T. and Rodriguez, Rosemarie and Albert, Marilyn and Onyike, Chiadi and D’Agostino, Daniel and Kielb, Stephanie and Sadowski, Martin and Sheikh, Mohammed O. and Singleton-Garvin, Jamika and Ulysse, Anaztasia and Gaikwad, Mrunalini and Doraiswamy, P. Murali and Petrella, Jeffrey R. and James, Olga and Borges-Neto, Salvador and Wong, Terence Z. and Coleman, Edward and Karlawish, Jason H. and Wolk, David A. and Vaishnavi, Sanjeev and Clark, Christopher M. and Arnold, Steven E. and Smith, Charles D. and Jicha, Greg and Hardy, Peter and Khouli, Riham El and Oates, Elizabeth and Conrad, Gary and Lopez, Oscar L. and Oakley, MaryAnn and Simpson, Donna M. and Porsteinsson, Anton P. and Martin, Kim and Kowalksi, Nancy and Keltz, Melanie and Goldstein, Bonnie S. and Makino, Kelly M. and Ismail, M. Saleem and Brand, Connie and Thai, Gaby and Pierce, Aimee and Yanez, Beatriz and Sosa, Elizabeth and Witbracht, Megan and Womack, Kyle and Mathews, Dana and Quiceno, Mary and Levey, Allan I. and Lah, James J. and Cellar, Janet S. and Burns, Jeffrey M. and Swerdlow, Russell H. and Brooks, William M. and Woo, Ellen and Silverman, Daniel H.S. and Teng, Edmond and Kremen, Sarah and Apostolova, Liana and Tingus, Kathleen and Lu, Po H. and Bartzokis, George and Graff-Radford, Neill R and Parfitt, Francine and Poki-Walker, Kim and Farlow, Martin R. and Hake, Ann Marie and Matthews, Brandy R. and Brosch, Jared R. and Herring, Scott and van Dyck, Christopher H. and Carson, Richard E. and Varma, Pradeep and Chertkow, Howard and Bergman, Howard and Hosein, Chris and Black, Sandra and Stefanovic, Bojana and Heyn, Chris (Chinthaka) and Hsiung, Ging-Yuek Robin and Mudge, Benita and Sossi, Vesna and Feldman, Howard and Assaly, Michele and Finger, Elizabeth and Pasternack, Stephen and Pavlosky, William and Rachinsky, Irina and Drost, Dick and Kertesz, Andrew and Bernick, Charles and Munic, Donna and Mesulam, Marek-Marsel and Rogalski, Emily and Lipowski, Kristine and Weintraub, Sandra and Bonakdarpour, Borna and Kerwin, Diana and Wu, Chuang-Kuo and Johnson, Nancy and Sadowsky, Carl and Villena, Teresa and Turner, Raymond Scott and Johnson, Kathleen and Reynolds, Brigid and Sperling, Reisa A. and Johnson, Keith A. and Marshall, Gad A. and Yesavage, Jerome and Taylor, Joy L. and Chao, Steven and Lane, Barton and Rosen, Allyson and Tinklenberg, Jared and Zamrini, Edward and Belden, Christine M. and Sirrel, Sherye A. and Kowall, Neil and Killiany, Ronald and Budson, Andrew E. and Norbash, Alexander and Johnson, Patricia Lynn and Obisesan, Thomas O. and Oyonumo, Ntekim E. and Allard, Joanne and Ogunlana, Olu and Lerner, Alan and Ogrocki, Paula and Tatsuoka, Curtis and Fatica, Parianne and Fletcher, Evan and Maillard, Pauline and Olichney, John and DeCarli, Charles and Carmichael, Owen and Kittur, Smita and Borrie, Michael and Lee, T-Y and Bartha, Rob and Johnson, Sterling and Asthana, Sanjay and Carlsson, Cynthia M. and Tariot, Pierre and Burke, Anna and Hetelle, Joel and DeMarco, Kathryn and Trncic, Nadira and Fleisher, Adam and Reeder, Stephanie and Bates, Vernice and Capote, Horacio and Rainka, Michelle and Scharre, Douglas W. and Kataki, Maria and Tarawneh, Rawan and Zimmerman, Earl A. and Celmins, Dzintra and Hart, David and Pearlson, Godfrey D. and Blank, Karen and Anderson, Karen and Flashman, Laura A. and Seltzer, Marc and Hynes, Mary L. and Santulli, Robert B. and Sink, Kaycee M. and Yang, Mia and Mintz, Akiva and Island, Rhode and Ott, Brian R. and Tremont, Geoffrey and Daiello, Lori A. and Bodge, Courtney and Salloway, Stephen and Malloy, Paul and Correia, Stephen and Lee, Athena and Rosen, Howard J. and Miller, Bruce L. and Perry, David and Mintzer, Jacobo and Spicer, Kenneth and Bachman, David and Finger, Elizabeth and Pasternak, Stephen and Rachinsky, Irina and Rogers, John and Kertesz, Andrew and Drost, Dick and Pomara, Nunzio and Hernando, Raymundo and Sarrael, Antero and Miller, Delwyn D. and Smith, Karen Ekstam and Koleva, Hristina and Nam, Ki Won and Shim, Hyungsub and Schultz, Susan K. and Relkin, Norman and Chiang, Gloria and Lin, Michael and Ravdin, Lisa and Smith, Amanda and Leach, Christi and Raj, Balebail Ashok and Fargher, Kristin and Weiner, Michael W. and Aisen, Paul and Weiner, Michael and Aisen, Paul and Petersen, Ronald and Green, Robert C. and Harvey, Danielle and Jack, Clifford R. and Jagust, William and Morris, John C. and Saykin, Andrew J. and Shaw, Leslie M. and Toga, Arthur W. and Trojanowki, John Q. and Neylan, Thomas and Grafman, Jordan and Green, Robert C. and Montine, Tom and Weiner, Michael and Petersen, Ronald and Aisen, Paul and Jimenez, Gustavo and Donohue, Michael and Gessert, Devon and Salazar, Jennifer and Cabrera, Yuliana and Walter, Sarah and Hergesheimen, Lindsey and Neylan, Thomas and Hayes, Jacqueline and Finley, Shannon and Harvey, Danielle and Donohue, Michael and Jack, Clifford R. and Bernstein, Matthew and Borowski, Bret and Gunter, Jeff and Senjem, Matt and Kantarci, Kejal and Ward, Chad and Jagust, William and Koeppe, Robert A. and Foster, Norm and Reiman, Eric M. and Chen, Kewei and Landau, Susan and Morris, John C. and Cairns, Nigel J. and Householder, Erin and Shaw, Leslie M. and Trojanowki, John Q. and Lee, Virginia and Korecka, Magdalena and Figurski, Michal and Toga, Arthur W. and Crawford, Karen and Neu, Scott and Saykin, Andrew J. and Foroud, Tatiana M. and Potkin, Steven and Shen, Li and Faber, Kelley and Kim, Sungeun and Nho, Kwangsik and Weiner, Michael W. and Friedl, Karl and Schneider, Lon S. and Pawluczyk, Sonia and Becerra, Mauricio and Brewer, James and Vanderswag, Helen and Stern, Yaakov and Honig, Lawrence S. and Bell, Karen L. and Fleischman, Debra and Arfanakis, Konstantinos and Shah, Raj C. and Duara, Ranjan and Varon, Daniel and Greig, Maria T and Doraiswamy, P. Murali and Petrella, Jeffrey R. and James, Olga and Porsteinsson, Anton P. and Goldstein, Bonnie and Martin, Kimberly S. and Potkin, Steven G. and Preda, Adrian and Nguyen, Dana and Mintzer, Jacobo and Massoglia, Dino and Brawman-Mintzer, Olga and Sadowsky, Carl and Martinez, Walter and Villena, Teresa and Jagust, William and Landau, Susan and Rosen, Howard and Perry, David and Turner, Raymond Scott and Behan, Kelly and Reynolds, Brigid and Sperling, Reisa A. and Johnson, Keith A. and Marshall, Gad and Sabbagh, Marwan N. and Jacobson, Sandra A. and Sirrel, Sherye A. and Obisesan, Thomas O. and Wolday, Saba and Allard, Joanne and Johnson, Sterling C. and Fruehling, J. Jay and Harding, Sandra and Peskind, Elaine R. and Petrie, Eric C. and Li, Gail and Yesavage, Jerome A. and Taylor, Joy L. and Furst, Ansgar J. and Chao, Steven and Relkin, Norman and Chiang, Gloria and Ravdin, Lisa and Mackin, Scott and Aisen, Paul and Raman, Rema and Mackin, Scott and Weiner, Michael and Aisen, Paul and Raman, Rema and Jack, Clifford R. and Landau, Susan and Saykin, Andrew J. and Toga, Arthur W. and DeCarli, Charles and Koeppe, Robert A. and Green, Robert C. and Drake, Erin and Weiner, Michael and Aisen, Paul and Raman, Rema and Donohue, Mike and Jimenez, Gustavo and Gessert, Devon and Harless, Kelly and Salazar, Jennifer and Cabrera, Yuliana and Walter, Sarah and Hergesheimer, Lindsey and Shaffer, Elizabeth and Mackin, Scott and Nelson, Craig and Bickford, David and Butters, Meryl and Zmuda, Michelle and Jack, Clifford R. and Bernstein, Matthew and Borowski, Bret and Gunter, Jeff and Senjem, Matt and Kantarci, Kejal and Ward, Chad and Reyes, Denise and Koeppe, Robert A. and Landau, Susan and Toga, Arthur W. and Crawford, Karen and Neu, Scott and Saykin, Andrew J. and Foroud, Tatiana M. and Faber, Kelley M. and Nho, Kwangsik and Nudelman, Kelly N. and Mackin, Scott and Rosen, Howard and Nelson, Craig and Bickford, David and Au, Yiu Ho and Scherer, Kelly and Catalinotto, Daniel and Stark, Samuel and Ong, Elise and Fernandez, Dariella and Butters, Meryl and Zmuda, Michelle and Lopez, Oscar L. and Oakley, MaryAnn and Simpson, Donna M.}, TITLE={The Influence of Cerebrospinal Fluid Abnormalities and APOE 4 on PHF-Tau Protein: Evidence From Voxel Analysis and Graph Theory}, JOURNAL={Frontiers in Aging Neuroscience}, VOLUME={11}, YEAR={2019}, URL={https://www.frontiersin.org/articles/10.3389/fnagi.2019.00208}, DOI={10.3389/fnagi.2019.00208}, ISSN={1663-4365}, 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.} }