Frontiers in Aging Neuroscience (Aug 2019)

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,
  • 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 (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,
  • 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

DOI
https://doi.org/10.3389/fnagi.2019.00208
Journal volume & issue
Vol. 11

Abstract

Read online

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.

Keywords