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

DOI=10.3389/fnagi.2019.00208

ISSN=1663-4365

ABSTRACT=<p>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, <italic>Q</italic> 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, <italic>Q</italic> 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.</p>