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Logo of neurologyNeurologyAmerican Academy of Neurology
 
Neurology. 2013 August 20; 81(8): 736–744.
PMCID: PMC3776464

Impaired default network functional connectivity in autosomal dominant Alzheimer disease

Jasmeer P. Chhatwal, MD, PhD,*

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Journal of Alzheimer's Disease, Associate Editor, 2013-

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) American Academy of Neurology, Clinical Research Training Fellowship, starting July 1, 2013

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Aaron P. Schultz, PhD,*

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. (1) NIH/NIA P01AG036694-01, Research Staff, 2010-2013, (2) NIH/NIA R01-AG027435 and R01-AG027435-S1, Research Staff 2009-2013

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Keith Johnson, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1) Pfizer Inc., travel and speaker honoraria

Editorial Boards:

  1. (1) Journal of Neuroimaging, Associate Editor, 2005-2012

Patents:

  1. NONE

Publishing Royalties:

  1. (1) The Whole Brain Atlas, Williams and Wilkins, 1999

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. 1) GEHC Ltd; 2) Avid/Lilly 3) Bayer-Schering; 4) Pfizer; 5) Elan/Janssen; 6) Bristol-Myers-Squib 7) Siemens 8) Piramal; 9) Genzyme

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical procedures or imaging studies:

  1. 1) Division of Nuclear Medicine and Molecular Imaging, Department of Imaging, Massachusetts General Hospital, Boston, MA., <5%, 2002-2011; 2) Memory Disorders Unit, Department of Neurology, Brigham and Women's Hospital, Boston, MA., <5%, 1993-2011.

Research Support, Commercial Entities:

  1. 1) Avid/Lilly; 2) Bristol-Myers-Squib; 3) Janssen (JanssenAI); 4) Pfizer 5) Navidea

Research Support, Government Entities:

  1. 1) NIH/NIA R01 AG037497, principal investigator, 2010- 2011; (2) NIH/NIA: R01 AG027435S, co-princpal investigator, 2005- 2011; (3) P50 AG00513421, co-investigator, 2002-2011; (4) P01 AG036694 co-principal investigator, 2009-2011; (5) R01 AG021910, co-investigator, 2008-2011; (6) K23 AG033634, sponsor/mentor, 2009-2011; (7) NIH/NINDS R01 NS062028, co- investigator, 2008-2011; (8) NIH/NINDS R01 AG026484, co- investigator, 2010-2011; (9) NIH/NIA R21 AG038994, co- investigator, 2011

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) Alzheimer Association ZEN-10-174210, principal investigator, 2010-2011; (2) Alzheimer Association IIRG-08-90934, co- investigator, 2008-2011; (3) American Health Assistance Foundation, co-investigator, 2010-2011

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Tammie L.S. Benzinger, MD, PhD,

Scientific Advisory Boards:

  1. (1) Eli Lilly Advisory Board (2011)

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. (1) Compensation for development of CME materials for Quintiles

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Investigator initiated research grants, Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly). Support for the research projects only, no personal compensation or salary support.

Research Support, Government Entities:

  1. (1) 5P01AG026276 (PI: J. Morris) 10/1/11-9/30/15 NIH/NIA Adult Children Study (ACS) Role: Project 4 Principal Investigator (T. Benzinger), (2)1 U01AG032438 (PI: J. Morris) 9/30/08-6/30/14, NIH/NIA, Dominantly Inherited Alzheimer Network (DIAN) Role: Core G (Imaging Core) Principal Investigator (T.Benzinger) (3) AG003991-27 (PI: J. Morris) 5/15/09-12/31/13 NIH/NIA HASD: Healthy Aging and Senile Dementia, Imaging Core (Core Director, T. Benzinger), (4) 1R01 NS066905-01 (PI: D. Marcus) 9/30/09 - 6/30/2014, NIH/NINDS, BIRN Resources Facilitate the Personalization of Malignant, Brain Tumor, Role: Co-Investigator, (5) 1R01 AG043434 (PI: C. Roe) 9/30/12-8/31/17, NIH, Title: Driving Performance in Preclinical Alzheimer's, Disease, Role: Co-investigator, (6) 1P01NS059560-01A1 (PI: A. Cross) 10/1/2008 - 7/31/12 NIH/NINDS, Title: Biomarkers and Pathogenesis of MS: From Mouse to Human Role: Co-Investigator, (7) Research Grant 6/01/10 - 6/31/12 Washington University Institute of Clinical and Translational Science, UL1 RR024992 Title: qBOLD MR measurements of oxygen extraction fraction in patients with brain tumors Role: Project PI

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) National Multiple Sclerosis Society, Research Grant. Legal Proceedings: (1) I have previously testified as a treating physician (not an expert witness).

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Clifford Jack, Jr, MD,

Scientific Advisory Boards:

  1. scientific advisory panels: Siemens

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other activities:

  1. Investigator in clinical trials sponsored by Baxter and Allon

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Allon and Baxter, perform MRI related services for clinical trial

Research Support, Government Entities:

  1. RO1 AG011378 PI; U01 AG024904-01 co-I; RO1 AG37551 co-I; 1U01HL096917 co-I; U01 AG032438 co-I; RO1 AG041851-01 co- PI Stock/Stock Options, Medical Equipment & Materials: Johnson and Johnson, 2010

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Beau M. Ances, MD, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Journal of Neurovirology

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Alzheimer's Association

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Caroline A. Sullivan, BA,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Stephen P. Salloway, MD,

Scientific Advisory Boards:

  1. Sanofi-Aventis, scientific advisory board, 2011-2012 Pfizer, scientific advisory board, 2005-12 Bristol Myers Squibb, scientific advisory board, 2007-12 Janssen AI, scientific advisory board, 2007-2013 Baxter, scientific advisory board, 2011-2013 GE Healthcare, 2012-2013 Avid-Lilly, 2012-2013, Grifols, 2013 Roche, 2012-2013, Merck, 2012-2013

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Athena Diagnostics-medical lectures 2005-12

Editorial Boards:

  1. Journal of Neuropsychiatry and Clinical Neurosciences, associate editor, 2005-12

Patents:

  1. NONE

Publishing Royalties:

  1. American Psychiatric Press Inc-The Frontal Lobes and Neuropsychiatric Illness and The Neuropsychiatry of Limbic and Subcortical Disorders Humana Press-Vascular Dementia

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Janssen AI and Pfizer phase 2 and phase 3, ACC phase 1, Wyeth-ACC phase 2, 2009-13 Bristol Myers Squibb-gamma secretase inhibitor phase 2, 2008-13 Genentech, monoclonal antibody phase 2, 2011-2013 GE,amyloid PET tracer, 2011-2012 Avid,amyloid PET tracer, 2011-2013 Merck,amyloid PET tracer, 2011-2012 Merck, beta secretase inhibitor, phase 2 Baxter phase 3 IVIg, 2012-2013 Biogen phase 2 monoclonal antibody, 2012-2013 Roche phase 2 monoclonal antibody, 2012-2013 Functional Neuromodulation, phase 2 DBS, 2013

Research Support, Government Entities:

  1. Alzheimer's Disease Neuroimaging Initiative, 2005-13 Dominantly Inherited Alzheimer's Network, 2008-13

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. The Norman and Rosalie Fain Family Foundation, 2006-13 The Champlin Foundation 2010-2012 The Happy White Family Foundation, 2010-2012 The Alzheimer's Association, 2010-2013

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
John M. Ringman, MD,

Scientific Advisory Boards:

  1. 1) Dr. Ringman has received compensation as an advisory board member for Takeda Pharmaceuticals 2) Dr. Ringman has received compensation as an advisory board member for StemCells, Inc.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. 1) Pfizer 2) Elan Pharmaceuticals 3) Bristol Meyers Squibb

Research Support, Government Entities:

  1. 1) Dr. Ringman receives research support from an Alzheimer's Disease Research Center Grant (AG016570), 2010-2015, Clinical Core Leader 2) Dr. Ringman receives research support the Dominantly Inherited Alzheimer Network (AG-032438) from the National Institute on Aging, 2008-2014, Site PI

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarker Development

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Robert A. Koeppe, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. 1. Avid Pharamceuticals 2. Merck 3. Johnson & Johnson

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Receive research support from Elan Pharmaceuticals.

Research Support, Government Entities:

  1. NIH grants # UO1 AG024904-01, PO1 NS15655, RO1 HL079540, RO1 DA022520, RO1 DA016423 Co-investigator on all grants

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Daniel S. Marcus, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. (1) Patent pending (U.S. Patent Application Serial No. 12/634,392) for a software system to select and perform automated medical imaging analysis

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. (1) Avid Radiopharmaceuticals, Inc.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Medtronic

Research Support, Government Entities:

  1. (1) Department of Defense, Investigator (2) NIH, U24 RR025736, Site PI (3) NIH, U01 AG032438-019008, Investigator (4) NIH, R01 MH074916, Investigator (5) NIH, P01 AG026276, Investigator (6) NIH, U54 EB005149, Investigator (7) NIH, P30 NS048056, PI (8) NIH, R01 EB009352, PI (9) NIH, R01 NS066905, PI

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Paul Thompson, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. 2003 - present Associate Editor or Editorial Board Member for: IEEE Transactions on Medical Imaging, Human Brain Mapping, Medical Image Analysis, Cerebral Cortex, Current Medical Imaging Reviews, Inverse Problems and Imaging, Translational Neuroscience

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Ongoing Research Support R01 EB008432 Thompson (PI) 09/30/09-08/31/13 NIH HARDI Mapping of Disease Effects on the Brain This project develops tools that unleash the full power of HARDI (high- angular resolution diffusion imaging) to advance clinical studies of the brain. HARDI applies magnetic field gradients to the brain in up to 256 different directions to precisely detail the directions, pathways, and integrity of fibers and their connections. Role: PI R01 EB008281 Thompson (PI) 12/01/07- 11/30/12 NIH/NIBIB A Multidimensional Alzheimer's Disease Brain Atlas This is a competitive renewal that will continue to provide the most powerful computational tools to scientists to track Alzheimer's disease emerging and spreading in the living brain – years before symptoms begin. Role: PI R01 EB007813 Thompson (PI) 08/01/07-04/30/11 NIH/NIBIB Computational Modeling of High-Field MR Images This project significantly extends the power of MRI and diffusion tensor imaging (DTI) at ultra-high magnetic field strengths (7T) to resolve previously unseen features of brain structure and fiber properties, providing unique power to investigate disease. Role: PI R01 HD050735 Wright (PI) 06/01/07- 05/31/12 NIH Genetic influences on the brain: A twin imaging study The long–term objective of this application is to characterize the differential roles of genes and environment in shaping brain structure and function, to map and identify the genes involved, and to characterize the impact of brain relevant genetic polymorphisms. Role: Subcontract PI RC2 AG036535 (Weiner) 09/30/09-08/31/11 Northern California Institute for Research & Education/NIH Amyloid Imaging, VMCI, and Analysis for ADNI In this project, we will analyze the scans to determine the 3D profile of structural deficits in the brain using tensor-based morphometry, a method we have developed in our laboratory. Role: Subcontract PI U54 RR021813 Toga (PI) 09/24/04-07/31/10 (NCTE) NIH/NCRR Center for Computational Biology (CCB) This is a proposal to establish a new Center for Computational Biology (CCB). Our goals are to apply computational and mathematical approaches to the study of genes, cells, systems and whole brain. Role: Project PI P41 RR013642 Toga (PI) 08/01/07-07/31/12 NIH/NCRR Computational Anatomy and Multidimensional Modeling This goal here is to extend current atlases of brain that assume a static morphology and prohibit the examination of time varying changes. We will develop the framework and tools to evaluate dynamic changes in brain structure and function including processes such as development, aging and progression of diseases. Role: Project PI R01 AG020098 (Lopez) 07/01/07-06/30/12 NIH Predictors of Alzheimer's disease in Mild Cognitive Impairment This proposal focuses on modifying the progression to AD from normal aging. Role: Subcontract PI Completed Research Support R21 EB001561 Thompson (PI) 05/01/03-02/28/07 NIH/NIBIB Algorithms to Map Disease & Genetic Effects on the Brain This project develops novel mathematics and computational algorithms for detecting genetic and disease effects on human brain structure. Role: PI

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Andrew J. Saykin, PsyD,

Scientific Advisory Boards:

  1. Siemens Healthcare

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1) Brain Imaging and Behavior, a Springer Journal, Editor-in-Chief, 2006-present.

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Commercial: (1) Baxter BioScience, (2) Bristol-Myers Squibb, (3) Eli Lilly, (4) Pfizer, Inc., (5) Siemens Healthcare; Non-profit: (1) Dartmouth Medical School, (2) University of Michigan, (3) University of Vermont, (4) Vanderbilt University.

Speakers' Bureaus:

  1. NONE

Other activities:

  1. (1) Eli Lilly and Company, received funding to provide post-doctoral training in neuroimaging.

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Siemens Medical Solutions, investigator-initiated research project support; (2) Welch Allyn, Inc., investigator-initiated research project support.

Research Support, Government Entities:

  1. NIH: R01 AG19771 (PI), R01 CA101318 (PI); R01 LM011360 (MPI); RC2 AG036535 (Genetics Core Leader), P30 AG10133 (PI and Neuroimaging Core Leader), U01 AG032984 (Site PI; Chair, Genetics Working Group); Indiana Economic Development Corporation: IEDC #87884 (PI)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) Foundation for the NIH (FNIH) (PI & co-PI)

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. (1) Expert consultant, United States of America, ex. Rel. Kenneth James Jones vs. Brigham and Women's Hospital et al, Civil Action No. 1:07-CV--11481-WGY, 2010-2013.
Stephen Correia, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Peter R. Schofield, PhD, DSc,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1) Jannsen-Cilag Australia, Speaker Fee.

Editorial Boards:

  1. (1) Psychiatric Genetics, Editorial Board member, 2002 - present, (2) Australian and New Zealand Journal of Psychiatry, International Advisory Board member, 2011 - present, (3) International Journal of Neuropsychopharmacology, Editorial Board member, 2011 - present.

Patents:

  1. Method for diagnosing and assessing a predisposition to bipolar affective disorder, Assigned to Garvan Institute of Medical Research, Serial No PCT/AU98/00439 granted in the USA, Australia, Canada and Europe. Priority date 10 June 1997.

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. Neuroscience Research Australia (a not for profit company), Executive Director & CEO.

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. This study (1) NIH Grant 1U01 AG032438-01, Site Investigator, 2008-2014. Other research support (2) NHMRC (Australia) Program Grant 1037196, Chief Investigator, 2013-2017, (3) NHMRC Project Grant, 1005769, Chief Investigator, 2011-2013, (4) NHMRC Enabling Grant, 401184, Chief Investigator, 2006-2012, (5) NHMRC Project Grant, 568807, Chief Investigator, 2009-2012, (6) NHMRC Project Grant, 630574, Chief Investigator, 2010-2012, (7) NHMRC Project Grant, 1023202, Chief Investigator, 2012-2014, (8) Australian Research Council Linkage Grant LP0883261, Chief Investigator, 2008-2012, (9) NIH Grant 1R01 NS052470-01A2, Subcontractor, 2007-2012, (10) NHMRC/ARC Program Grant, 401162, Chief Investigator, 2007- 2011, (11) NHMRC CCRE Grant, 455431, Chief Investigator, 2007- 2011, (12) Australian Research Council Linkage Grant LP120200075, Chief Investigator, 2012-2015.

Research Support, Academic Entities:

  1. (1) University of New South Wales.

Research Support, Foundations and Societies:

  1. (1) Beyondblue National Priority Driven Research Project Grant, (2) Wicking Trust Grant #13026.

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Christopher C. Rowe, MD,

Scientific Advisory Boards:

  1. 1.GE Healthcare

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. GE Healthcare, honoraria Navidea, travel costs

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. 1. Bayer Schering Pharma 2. Avid Radiopharmaceuticals 3. Astra Zeneca 4. GE Healthcare

Research Support, Government Entities:

  1. Science Industry Endowment Fund, sponsor of the AIBL study 2011-2013.

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. 1. Alzheimer's Association 2. Alzheimer's Drug Discovery Foundation 3. Fidelity Foundation

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Nick C. Fox, MD,

Scientific Advisory Boards:

  1. (1) Bristol-Myers Squibb, Advisory Board, 2010, 2011, 2012; (2) Eisai Inc, Advisory Board, 2011; (3) GE Healthcare Advisory Board, 2011, 2012 (4) AVID (subsidiary of Eli Lilly), 2011; (5) Johnson & Johnson, 2010; (6) Janssen Alzheimer's Immunotherapy, 2011 (7) Eli Lilly Research Laboratories, 2012

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1) Alzheimer's Disease and Associated Disorders - Editorial Board 2004 to present; (2) Neurodegenerative Diseases - Editorial Board - 2004 to present; (3) Alzheimer's Research and Therapy - Editorial Board - 2008 to present

Patents:

  1. QA Box; Application PCT/GB2008/001537; Filed 4 May 2007

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. I have provided consultancy to the following companies. I did not receive personal compensation for this however consultancy fees were paid to our research group. AVID; Bristol-Myers Squibb, Bioclinica Inc; Elan Pharmaceuticals; Eli Lilly & Co, GE Healthcare; IXICO; Janssen Pharmaceuticals; Lundbeck; Pfizer Inc; Novartis; Wyeth Pharmaceuticals.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Payments were made to the Dementia Research Centre (no personal compensation to me) for contracted research - image analysis of multi-centre studies. Over the last 2 years these included Elan/Wyeth; Lundbeck; IXICO; Pfizer; Janssen; Wyeth

Research Support, Government Entities:

  1. MRC - PI - [Grant G0801306] - 2009-13; Grant [G0601846] - 2007-2012; NIH - Co-investigator - Grant [U01 AG024904] - 2005-2014; NIHR Senior Investigator - 2009-2013 [Five year term]

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Adam M. Brickman, PhD,

Scientific Advisory Boards:

  1. Currently serve on the scientific advisory board of Keystone Heart.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Editorial board member of The Journal of the International Neuropsychological Society. Editorial board member of Neuropsychology Review

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Consultant for ProPhase. Years: 2007-2011 and 2013-present. Consultant for Keystone Heart. Years: 2012-Present.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. grant support: NIH AG029949 PI 2007-2012 NIH AG024708 PI 2004-2006 NIH AG034189 PI 2010-2015 NIH AG043337 PI 2012-2014

Research Support, Academic Entities:

  1. grant support: Columbia University PI 2008-2009 Columbia University PI 2012-2013

Research Support, Foundations and Societies:

  1. grant support: Alzheimer's Association PI 2005-2007 Alzheimer's Association PI 2010-2012 Mary E. Groff Surgical Medical Research and Education Charitable Trust PI 2012-2013

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Richard Mayeux, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. RO1 AG037212 Epidemiology of Biomarkers of Risk and Progression in Late onset Alzheimer's Disease. Principal Investigator

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Eric McDade, DO,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Alzheimer Association, speaker honorarium, 2012.

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. Mild Cognitive Impairment I and II, UpToDate Inc., 2010- 2013.

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Dominantly Inherited Alzheimer Network Therapeutics Trial Unit

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. P50 AG05133 (PI Lopez, OL) (NIA/NIH)-University of Pittsburgh Alzheimer Disease Research Center; Co-Investigator. 1R01 MH080240 (PI Butter,M) (NIH)-Amyloid, White Matter Hyperintensities & Outcomes of Late-Life Depression; Co- investigator. 5U01 AG032438 (PI Morris, J) NIH/NIA- Dominantly Inherited Alzheimer Network; Site PI.

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. The Janet C. Thompson Research Fund and Robert N. Kohman Trust for Medical Assistance and Research of The Pittsburgh Foundation.

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Randall Bateman, MD,

Scientific Advisory Boards:

  1. (1) Envivo Scientific Advisory Board (2) 2009-present Alzheimer 's disease Cooperative Study (ADCS - 5U01AG010483-20) Steering Committee Member representing Washington University (3) 2009-present National Alzheimer's Disease Neuroimaging Initiative Industry Scientific Advisory Board Amyloid- Subteam member (4) 2011-present German Center for Neurodegenerative Diseases (DZNE), Frankfurt University Partner Site, External Advisory Board member

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1) Centers for Medicare & Medicaid Services - travel and hotel.(1/30/2013) (2)Salk Institute for Biological Studies - Adler Meeting - travel and hotel. (2/2/13) (3) Alzheimers Leadership Summit Meeting - Alzheimer's Assn. - travel and hotel. (2/7/13) (4) University of California @ San Diego/Alzheimers Disease Cooperative Study Steering Committee Meeting - travel and hotel (3/16/13) (5) Foundation for the National Institutes of Health - travel and hotel (4/30/13) (6) Takeda Alzheimers Disease Mtg - travel and hotel (12/2012) (7) Alzheimer's Prevention Initiative Advisory Board Meeting, Invited speaker – travel and hotel (2011) (8) Neuroscience Research Australia (NeuRA) Invited Seminar Series, Invited speaker – travel and hotel (2011) (9) Alzheimer's Association, Alzheimer's Imaging Consortium (AIC) 2012, Keynote Presenter – travel and hotel (10) 3rd International CAA Conference: Cerebral Amyloid Angiopathy and related Microangiopathies, Invited Speaker (2012) – travel and hotel (11) University of California @ San Diego/ADCS Steering Committee Meeting (2012) - travel and hotel (12) Takeda Science Foundation (2012) - travel and hotel (13) Merck - To discuss DIAN Trials and to provide consultation for Merck AD programs (2012) - travel and hotel (14) Biogen Idec - To discuss DIAN Trials (2012) - travel and hotel

Editorial Boards:

  1. Alzheimer's Research and Therapy, Editorial Board 2009- present

Patents:

  1. (1) Cofounder of C2N Diagnostics - developed the technology used in vivo stable isotop labeling to follow the production and clearance of proteins and other biomolecules in the human cerebrospinal fluid and brain. Patent #7,892,845

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. Washington University School of Medicine Charles F. and Joanne Knight Distinguished Professor of Neurology Principle Investigator, Department of Neurology Director, Dominantly Inherited Alzheimer's Network Trials Unit

Consultancies:

  1. (1) Novartis - 2011 (2) EnVivo - 2012 (3) Merck - 2012 (4) BioGen - 2012

Speakers' Bureaus:

  1. (1) Elan (2) Astra Zeneca

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) DIAN-TU Trial (Eli Lilly, Roche Pharma, Alz Assn) (2) Eli Lilly research collaboration (3) Merck research collaboration (4) AstraZeneca research collaboration (5) Alzheimer's Association (6)DIAN Pharmaceutical Consortium • Biogen Idec • Elan Pharmaceuticals, Inc. • Eli Lilly and Company • Hoffman La-Roche, Inc. • Genetech, Inc. • Janssen Alzheimer Immunotherapy • Mithridion, Inc. • Novartis Pharm AG • Pfizer Biotherapeutics Research & Development • Sanofi-Aventis

Research Support, Government Entities:

  1. NIH R01NS065667, PI, 5 years NIH P50AG00568, Project Leader, 5 years NIH U01AG032438, Site Leader and Clinical Core Leader, 5 years

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) American Health Assistance Foundation (2) Ruth K. Broad Biomedical Research Foundation Anonymous Foundation

Stock/Stock Options/Board of Directors Compensation:

  1. C2N Diagnostics

License fee payments, Technology or Inventions:

  1. C2N Diagnostics, Washington University

Royalty Payments, Technology or Inventions:

  1. C2N Diagnostics, Washington University

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Anne M. Fagan, PhD,

Scientific Advisory Boards:

  1. Advisory Board: 1) Lilly 2) Roche There are no conflicts of interest

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. 1) 6,465,195 B2 10/15/2002 “Predictive diagnostic for Alzheimer's disease” David Holtzman, Anne Fagan Niven, Steve Younkin, Linda Younkin 2) PCT/US09/050255 (7/10/2009, in process) “A risk factor and new therapeutic target for Alzheimer's disease” Alison Goate, Carlos Cruchaga, David Holtzman, Anne Fagan Niven

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. 1) Guidepoint Global (consultation on CSF biomarkers) 2) Wolters Kluwer (consultation on CSF biomarkers) 3) Coalition Against Major Diseases (CAMD)

Speakers' Bureaus:

  1. Speaker for the Alzheimer's Association, 2005

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. 1) P01 AG026276 (PI: Morris), years 6-10 9/30/11-9/30/16 NIH/NIA Antecedent biomarkers for AD: The Adult Children Study Goal: The major goal of this project is to identify antecedent biomarkers of Alzheimer's Disease. Role: Dr. Fagan Niven is the Biomarker Core Leader and the Project Leader for Project 2: “CSF biomarkers of antecedent AD” 2) U01AG032438 (PI: Morris), years 1-6 9/15/08 - 6/30/14 NIH/NIA Dominantly Inherited Alzheimer Network (DIAN) Goal: The goals of this international, multi-center study is to identify antecedent fluid biomarkers of Alzheimer's disease in families carrying autosomal-dominant AD mutations Role: Dr. Fagan Niven is the DIAN Biomarker Core Leader 3) R37AG013956 (PI: Holtzman), years 9-14 9/1/04-7/31/14 NIH/NIA Effect of ApoE on CNS Neurons: Role of LRP Goal: The major goals of this project are to study apoE/A interactions and the role of apolipoprotein E and A, and LDL receptors in AD neuropathology in APP transgenic mice. Role: Dr. Fagan Niven is Co-investigator 4) PO1AG003991 (PI: Morris), years 26-30 01/01/09-12/31/13 NIH/NIA Healthy Aging and Senile Dementia Goal: The goal of this project is to determine CSF biomarkers for predicting dementia and dementia progression. Role: Dr. Fagan Niven is Co-Investigator for Project 2: “CSF Biomarkers of Antecedent AD” 5) R01 AG043434 (Roe) 9/30/12 – 8/31/17 NIH Driving Performance In Preclinical Alzheimer's Disease Role: Co-Investigator 6) 12243040 (Bateman) 2/1/12 – 1/31/16 Alzheimer's Association Dominantly Inherited Alzheimer Network (DIAN) Trials Unit Role: Biomarker Core Leader

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Allison M. Goate, DPhil,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. Pfizer 2010 honorarium, Amgen 2012 honorarium, Rainwater Foundation 2013 honorarium, American Academy of Neurology 2013 honorarium

Editorial Boards:

  1. Alzheimer's Research and Therapy Ed Adv Board 2012

Patents:

  1. Tau mutations in FTD, TDP43 mutations in ALS\FTD

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Amgen 4/1/13

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. AstraZeneca Genentech Pfizer iPierian

Research Support, Government Entities:

  1. NIA 5R01AG016208-11 (Goate) PI 4/1/99-8/31/11, NIA 1R01AG035083-01 (Goate) PI 9/1/10-8/31/15, NIA 2P01AG03991-26 (Morris\Goate) Co-investigator 5/1/09-4/30/14, NIA 1U01AG032984-01 (Schellenberg\Goate) Co-Investigator, 4/1/09-3/31/14, NIA 2P50AG005681-27 (Morris) Co-Investigator 6/15/97-4/30/15, NIA 1U54MH091657-01 (Van Essen) Co-Investigator 9/15/10-8/31/15 NIDA 5R01DA012854-09 (Madden) Co-Investigator 5/25/00-4/30/13 NCI 5P01CA89392-07 (Bierut\Goate) Co-Investigator 12/1/00-6/30/13 NIA 5U01AG032438-02 (Morris) Co-Investigator 9/15/08-6/30/14 NIAAA 5U10AA08401-22 (Bierut) Co-Investigator 9/29/89-8/31/14

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. American Health Assistance Foundation (Bright Focus)

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. taconic tau mutation patent

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. Howrey 2010 Finnegan 2011/2012 Dickstein Shapiro 2011
Chengjie Xiong, PhD,

Scientific Advisory Boards:

  1. External Advisory Committee member of University of Wisconsin Alzheimer Disease Research Center; External Advisory Committee member of Mayo Clinc Study of Aging; statistical consultant for C2N Diagnostics; statistical consultant fot Cancer Treatment Centers of America; statistical consultant for Biogen Idec.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Associate Editor: Neuroscience and Biomedical Engineering 2012--present Associate Editor: Journal of Biometrics & Biostatistics 2010--present Invited member of Statistical Advisory Board: PLOS ONE 2013 - present Associate Editor of Biostatistics: Alzheimer's Disease & Associated Disorder 2005-6/30/2007 Associate Editor: Journal of the Alzheimer's Disease (2003-2004) Special Society Journal Reviewer: Alzheimer's & Dementia: the Journal of the Alzheimer's Association 2012--present Editorial board member: Journal of Modern Applied Statistical Methods;

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NIH/NIA R01 AG034119; NIH/NIA R01 AG038656; NIH/NIA P01AG26276-01; NIH/NIA 5 P01 AG03991; NIH/NIA 5P50 AG05681; NIH U01 AG16976; NIH/NIA 1U01 AG032438; NIH R01 AG029672

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Alzheimer Association New Investigator Research Award (NIRG)

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Virginia D. Buckles, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Role: Investigator Title: Dominantly Inherited Alzheimer Network (DIAN); U01AG032438 ,Morris, JC, PI Duration: 09/15/08 – 06/30/14 Role: Investigator Title: Healthy Aging and Senile Dementia (HASD); P01 AG03991 ,Morris, JC, PI Duration: 01/01/09 - 12/31/13 Role: Investigator Title: Alzheimer's Disease Research Center (ADRC); P50 AG05681 ,Morris, JC, PI Duration: 5/01/05 - 4/30/10 Role: Investigator Title: Antecedent Biomarkers for AD: The Adult Children Study (ACS); P01AG026276 ,Morris, JC, PI Duration: 7/01/05 – 6/30/10 (no cost extension)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Fidelity Foundation (wishes to remain anonymous)

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
John C. Morris, MD,

Scientific Advisory Boards:

  1. SABs for the following pharmaceutical and biotechnology companies in 2012-2013: Eisai; Janssen Alzheimer Immunotherapy Program; GlaxoSmithKline; Novartis; Pfizer Inc.; Eli Lilly/Avid Radiopharmaceuticals

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Serves on the editorial advisory board of Annals of Neurology, ADAD, Dementia & Neuropsychologia

Patents:

  1. NONE

Publishing Royalties:

  1. 1. Blackwell Publishing, 2009, for Burns J and Morris JC, “Mild Cognitive Impairment and Early Alzheimer's Disease”, copyright 2008 by John Wiley and Sons, Ltd 2. Taylor & Francis 2008; “Handbook of Dementing Illnesses, 2 Ed”, Morris JC, Galvin JE, Holtzman DM, Eds, copyright 2006 4. Elsevier 2008, for Editorial in Lancet Neurology 2008

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Receives research support from Eli Lilly/Avid Radiopharmaceuticals

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
and Reisa A. Sperling, MDcorresponding author

Scientific Advisory Boards:

  1. 1) Satori Pharmaceuticals - commercial entity

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Has served as a consultant for 1) Roche (unpaid; commercial entity), 2) Janssen (unpaid; commercial entity); 3) Pfizer (unpaid; commercial entity), 4) Eisai (commercial entity), 5) Eli Lilly (unpaid; commercial entity), 4) Bristol-Myers Squibb (commercial entity) and 7) Avid Radiopharmaceuticals (unpaid; commercial entity).

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Janssen, clinical trial investigator 2008-2012; investigator-initiated imaging study, 2012-2014. Bristol-Myers-Squibb, clinical trial investigator 2009-2012

Research Support, Government Entities:

  1. 1) National Institute on Aging R01AG027435, Principal investigator, 2006-2012; 2) National Institute on Aging P01AG036694, principal investigator, 2010-2015. 3) National Institute on Aging P50 AG005134, 2008-2013;Project leader. 4) National Institute on Aging U19 AG10483, Project Leader A4 trial, 2012-2017.

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. American Health Assistance Foundation, principal investigator, 2010. Alzheimer's Association, co-principal investigator, 2012-2013

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Abstract

Objective:

To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.

Methods:

Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).

Results:

We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.

Conclusion:

Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive synaptic failure.14 Recent advances in functional neuroimaging techniques allow for the indirect assessment of polysynaptic connections in the human brain. Analyses of coordinated, spontaneous, blood oxygen level–dependent signal fluctuations during task-independent fMRI (termed resting-state functional connectivity MRI [fcMRI]) have demonstrated the presence of ubiquitous large-scale neural networks.57 Of particular relevance to AD is a set of cortical regions collectively known as the default mode network (DMN).4,811

Intact functional connectivity within the DMN at rest, as well as the ability to modulate DMN activity during memory encoding and retrieval tasks, is thought to be critical for successful memory function.12,13 The DMN includes the posterior cingulate, lateral parietal, and medial frontal cortices. The neocortical regions of the DMN are preferential (but not exclusive) sites for amyloid-β (Aβ) deposition in early AD.14 Studies in sporadic late-onset AD (LOAD) have demonstrated decreases in DMN fcMRI.2,4 Similar changes are also seen in prodromal and preclinical AD, as evidenced by decreased DMN fcMRI in subjects with mild cognitive impairment (MCI) who progress to AD,11 asymptomatic APOE ε4 carriers,1517 and Aβ biomarker–positive older individuals.1820

Together, these findings have prompted the development of DMN connectivity as a noninvasive biomarker for detection of early synaptic dysfunction in AD and for tracking potential therapeutic response in clinical trials. Despite being well studied in the symptomatic stages of LOAD,2,4 alterations in DMN fcMRI have been largely unstudied in cases of familial autosomal dominant AD (ADAD).

In the present report, we examine changes in DMN fcMRI across the continuum of impairment in a large cohort of subjects drawn from 8 international sites within the Dominantly Inherited Alzheimer Network (DIAN).21,22 This cohort of subjects presents a rare opportunity to examine fcMRI across the spectrum of AD in a young group of subjects carrying highly penetrant ADAD mutations. Taking advantage of the relatively conserved age of dementia onset within each family,2325 we also model changes in DMN connectivity regarding each subject's estimated years from expected symptom onset (eYO) in their families to generate a temporal pattern for altered DMN fcMRI in ADAD.

METHODS

Participants, standard protocol approvals, registrations, and participant consents.

Persons with first-degree relatives known to carry ADAD mutations in presenilin-1 (PSEN1), presenilin-2 (PSEN2), or amyloid precursor protein (APP) were recruited into the DIAN study (www.dian-info.org; NIA-U19-AG032438, Clinical Trial Identifier NCT00869817) irrespective of ADAD mutation status. All subjects provided informed consent in accordance with the local institutional review boards of each participating site. A detailed protocol for the DIAN study has previously been published, and is available in the supplementary data of reference 22.

Cross-sectional clinical and imaging data from 120 people from 61 families, including 83 carriers of ADAD mutations (PSEN1: 68; PSEN2: 5; APP: 10) collected at 8 DIAN sites were analyzed. Comparisons were made to a control group of 37 asymptomatic, mutation-negative subjects from the same families. Four mutation-negative individuals with Clinical Dementia Rating (CDR) ≥0.5 were not included because of their low number and ambiguity regarding their underlying diagnosis. The remaining 120 subjects were classified into 4 groups on the basis of mutation and CDR status (table 1): asymptomatic mutation-negative participants (CDR 0M−), asymptomatic mutation carriers (CDR 0M+), early symptomatic mutation carriers (CDR 0.5M+), and mutation carriers with clinical dementia (CDR 1–2M+). Only baseline data available in the DIAN database as of February 2012 were included in this study.

Table 1
Participant demographics

Clinical evaluation.

Participants underwent an extensive evaluation, including physical examination, cognitive testing, and CDR, in which a score of 0 indicates no dementia, 0.5 indicates questionable or very early dementia, and 1, 2, and 3 correspond to mild, moderate, and severe dementia, respectively. DIAN investigators were blinded to participant mutation status in asymptomatic individuals and received no confirmation of genetic status in symptomatic individuals. Outside of medical necessity, no research data (including genetic status) were provided to participants as part of the DIAN study. Participants wishing to know their mutation status were offered free-of-charge genetic counseling, separate from the conduct of the study.

Using semistructured interviews with cognitively intact family members, each participant's eYO was computed as the subject's age minus the age at which the subject's parent or sibling first showed symptoms of progressive cognitive decline22 (familial age at onset). In cases in which multiple first-degree relatives were available to calculate familial age at onset, an average value was used. Accordingly, negative eYO values indicate participants younger than the age at which his/her parent or sibling(s) developed the first signs of progressive cognitive decline.

Genetic analysis.

DNA was extracted from blood samples sent to the DIAN Genetics Core (DGC) at Washington University and the National Cell Repository for Alzheimer's Disease (NCRAD). For quality control purposes, sequencing for DIAN mutations and APOE genotyping (using rs7412 and rs429358 as markers) and DNA fingerprinting was performed by DGC personnel in parallel on DNA samples extracted by DGC and NCRAD. Only subjects with concordant data for DGC and NCRAD extractions were included in the analysis.

Imaging methods.

Data acquisition.

Participants underwent eyes-open resting-state fMRI using a 12-channel phased-array head coil. Earplugs and noise-reduction headphones were used to attenuate scanner noise, and head motion was minimized with foam padding. Only data from Siemens Trio TIM 3T (109 sessions) or Verio 3T (11 sessions) scanners (Siemens Medical Solutions, Erlangen, Germany) were used in this report. Trio TIM Data were acquired using a gradient-echo echo-planar pulse sequence sensitive to blood oxygen level–dependent contrast using the following parameters: repetition time = 2,200 milliseconds; echo time = 30 milliseconds; fractional anisotropy = 80°; 64 × 64 matrix; 3.125 × 3.125 mm in-plane resolution with 3.3 mm slice thickness, with equivalent parameters used on the Verio. Thirty-six interleaved axial slices covered a field of view of 119 mm. Images were acquired in a single run of 120 time points, lasting approximately 5 minutes.

Preprocessing.

Using SPM8 (http://www.fil.ion.ucl.ac.uk/spm/; version r4290) each run was slice-time corrected, realigned to the first volume of each run with INRIAlign,26,27 normalized to the Montreal Neurological Institute (MNI) ICMB152 EPI template, and smoothed with a 6-mm full width at half maximum Gaussian kernel. Realignment parameters were used to calculate the mean movement across the resting-state MRI, which was then used to screen out sessions with excessive movement using a threshold set at 0.15 mm/repetition time.28 This resulted in the exclusion of 14 subjects (8 CDR 0M−, 4 CDR 0M+, 1 CDR 0.5M+, and 1 CDR 1–2M+), leaving a total of 120 subjects.

Functional connectivity analysis.

Group spatiotemporal independent component analysis (ICA) was performed using the GIFT toolbox (http://mialab.mrn.org/software/gift/;v1.3h) for MATLAB. The SPM gray matter template with a probability threshold of 0.30 was used to mask out extra gray matter voxels. First-pass principal component analysis using 40 components per session was followed by use of the Infomax algorithm to generate 20 independent components. The GICA3 algorithm29 was used to back-construct spatial component maps and time courses for each subject. A goodness-of-fit approach4 was used to quantitatively identify the component that most accurately matched a DMN template created from an independent set of young subjects using 10-mm spherical precuneus/posterior cingulate (PPC) (MNI coordinates: 0, −53, 26) seed-based maps. Similar fcMRI analysis of the motor network was performed to determine whether fcMRI was universally altered across networks in mutation carriers.

Statistical analyses.

Given the lack of a sufficient group of individuals who were CDR >0M− to assess for a classic interaction between CDR and mutation status, we ran 3 separate general linear models (GLMs). The first GLM was a simple 1-way analysis of variance (ANOVA) across the 4 groups described above (CDR 0M−; CDR 0M+; CDR 0.5M+; CDR >0.5M+). The second GLM was an analysis of covariance modeled as eYO × mutation, which allowed for the assessment of an interaction between the eYO variable and the presence of an ADAD mutation. As a final check, we performed this second analysis while controlling for CDR to evaluate the additional explanatory contribution of the model beyond what could be explained by CDR status alone.

Importantly, we also investigated the influence of family membership, performance site, APOE, and nonlinear terms for eYO, as well as the appropriateness of the eYO construct relative to the inclusion of both age and familial age at onset as separate regressors (see supplemental data on the Neurology® Web site at www.neurology.org). We found no contribution of family membership (modeled as a random effect), APOE, sex, and nonlinear eYO terms to the models. Additionally, we visualized the relationship between eYO and PPC fcMRI using local regression (LOESS) to facilitate comparison with earlier reports from DIAN (figure e-1).

Lastly, we evaluated whether performance site was a substantial contributor to the observed findings (see e-Methods, table e-1). Given the similarity of results when site was included or excluded in the model, we did not include site as a covariate in the primary analyses (in keeping with prior reports from DIAN in which site was not used as a covariate22). Backward elimination was used to evaluate the utility of additional model terms and resulted in the following final model: connectivity = eYO + mutation + (eYO × mutation), which was used for the analyses presented below.

RESULTS

Demographics.

As expected, asymptomatic mutation carriers were significantly younger on average than symptomatic mutation carriers and further from their expected age of symptom onset (see table 1). In our cohort, asymptomatic non–mutation carriers were modestly but significantly older than asymptomatic mutation carriers (p = 0.033). No significant differences in APOE ε4 carrier status were observed across groups. Modest but statistically significant differences in Mini-Mental State Examination scores between CDR 0M− and CDR 0M+ groups were observed.

ICA analysis of task-free fMRI data.

ICA analysis including all subjects who were M+ and M− revealed a single, easily identifiable DMN, including the PPC cortices, medial prefrontal cortex (mPFC), lateral parietal regions (left lateral parietal cortex [LPC] and right lateral parietal cortex [RPC]), lateral temporal regions, and bilateral medial temporal regions (medial temporal lobe; figure 1). Although not examined in detail, several previously described neural networks appeared in our ICA analysis. Among these, the motor network was analyzed to determine whether general changes in fcMRI in mutation carriers were present. No significant changes in motor network fcMRI were seen at p < 0.005 (not shown), arguing against universally decreased fcMRI in mutation carriers.

Figure 1
DMN component derived from group ICA

ANOVA comparing DMN fcMRI across groups.

One-way ANOVA across groups defined by mutation and clinical status demonstrated decreased functional connectivity within much of the DMN in ADAD mutation carriers compared with noncarriers (figure 2, A–E, and figure 3A). Decreased connectivity was most apparent within the major posterior node of the DMN (PPC; F3,116 = 14.72, p < 0.001; figure 2, A and B), along with significantly decreased connectivity in the anterior node of the DMN (mPFC; F3,116 = 10.10, p < 0.001; figure 2, A and C). Significant differences were also observed in the lateral parietal cortices (RPC: F3,116 = 10.09, p < 0.001; LPC: F3,116 = 11.92, p < 0.001) as well as numerous other peaks within the DMN (table e-2).

Figure 2
Whole-brain analysis of variance
Figure 3
Decreasing DMN connectivity as subjects approach and surpass their expected age of symptom onset

Post hoc comparison of CDR 0M− with CDR 0.5M+ and CDR 1–2M+ demonstrated that DMN functional connectivity was decreased in the PPC, mPFC, LPC, and RPC in symptomatic mutation carriers as compared with asymptomatic non–mutation carriers (figure 2, A–E). Post hoc comparison of asymptomatic mutation carriers with noncarriers (i.e., CDR 0M+ with CDR 0M− groups) yielded significantly decreased functional connectivity in the PPC (t79 = 2.51; p = 0.014; figure 2, A and B) and RPC (t79 = 3.28; p = 0.0016; figure 2, A and E), but these effects were relatively modest in size.

Post hoc comparisons demonstrated decreases in functional connectivity with advancing CDR in the PPC (CDR 0M+ vs CDR 0.5M+, t66 = 3.88; p < 0.001; CDR 0M+ vs CDR 1–2M+, t57 = 4.04; p < 0.001), mPFC (CDR 0M+ vs CDR 0.5M+, t66 = 3.94; p < 0.001; CDR 0M+ vs CDR 1–2M+, t57 = 4.49; p < 0.001), and RPC (CDR 0M+ vs CDR 0.5M+, t66 = 1.06; p = 0.295; CDR 0M+ vs CDR 1–2M+, t57 = 2.47; p = 0.016) nodes of the DMN. A more complex pattern was seen in the LPC, where asymptomatic mutation carriers showed very similar levels of connectivity compared with asymptomatic noncarriers (CDR 0M+ vs CDR 0M−, t79 = 0.05; p = 0.96), but decreases in connectivity were seen at higher CDRs (CDR 0M− vs CDR 0.5M+, t66 = 4.50; p < 0.001; CDR 0M− vs CDR 1–2M+, t57 = 3.80; p < 0.001).

Decreased connectivity as a function of proximity to familial age at symptom onset.

We next focused on examining the rate and pattern of degraded connectivity within the DMN by plotting changing DMN fcMRI against eYO. The strongest effect was seen in the PPC where we observed a significant interaction between mutation carrier status and eYO (t116 = 3.86, p = 0.017), with a significant negative correlation between fcMRI and eYO in mutation carriers (r = −0.59, t81 = −6.64; p < 0.001), but no significant relationship observed in noncarriers (r = −0.11, t35 = 0.06; p = 0.95; figure 3 and table 2). The relationship between eYO and fcMRI in mutation carriers remained significant after controlling for CDR status (PPC: r = −0.412, t79 = −2.39; p = 0.010). Similar patterns were observed in the mPFC, LPC, and RPC (figure 3, table 2).

Table 2
Correlations with estimated years from expected symptom onset

DISCUSSION

In the present study, we observed alterations in DMN connectivity in both symptomatic and asymptomatic carriers of pathogenic mutations in PSEN1, PSEN2, and APP. Connectivity within the DMN is decreased in symptomatic carriers of ADAD mutations and this decrease is greater in magnitude in more advanced disease. DMN fcMRI differs in asymptomatic mutation carriers as compared with noncarriers, with subtle decreases in DMN connectivity observable before symptom onset. A negatively sloped, mutation status–dependent decrease in DMN fcMRI is observed as mutation carriers approach and surpass their expected age of symptom onset, even when controlling for CDR. Although further study is needed to assess the test-retest reliability of fcMRI and to compare its performance with other biomarkers in early AD, these results suggest that DMN fcMRI may prove useful as a noninvasive biomarker for tracking disease progression in the preclinical30,31 and early clinical phases of ADAD. Additionally, these data demonstrate the feasibility of performing multicenter clinical trials using resting-state fcMRI, and support the inclusion of fcMRI as an exploratory outcome measure in upcoming AD prevention trials.21,31

Our study benefits from the unique strengths of the large DIAN cohort. Specifically, the relative youth of these subjects (as compared with the older populations studied in LOAD) allowed us to decrease the influence of “normal” age-related decreases in DMN functional connectivity,3,32 allowing for the clearer interpretation of decreasing DMN connectivity related to progression of AD rather than age. This is especially true as mutation noncarriers in our cohort were members of the same families as mutation carriers, lessening the possibility that polygenic variation outside of PSEN1, PSEN2, and APP are contributing to decreased DMN connectivity. However, the present study is limited in its ability to assess mutation-specific effects, given that our results are largely based on individuals carrying PSEN1 mutations. Notably, the observation of decreased fcMRI before symptom onset is consistent with CSF-based biochemical markers in both ADAD22,33 and in LOAD,34 where both CSF Aβ and tau abnormalities are manifest years before the onset of clinical symptoms. While the present study focuses on an initial description of fcMRI in ADAD and its potential use as a biomarker in clinical trials, additional studies are under way to examine connectivity changes in other networks and subnetworks, to place changes in fcMRI in temporal relation with respect to other biomarkers (especially CSF tau, Aβ, and PET amyloid imaging) and to compare the variability in fcMRI measures with that seen with other biomarker measures in this unique cohort. Finally, follow-up reports on longitudinal changes in fcMRI in this cohort are needed to more robustly evaluate the nature of DMN dysfunction with disease progression.

Modeling of DMN connectivity as a function of eYO benefits from the extremely high penetrance of ADAD mutations, despite the approximate nature of the eYO measure. The relative certainty that mutation carriers (regardless of cognitive status at the time of enrollment) will develop AD contrasts with similar studies in LOAD, where progression to AD dementia in MCI populations is quite variable35 and it is possible that subjects with MCI will develop other types of dementia. In this context, the high penetrance of ADAD mutations allows us to more confidently model changes in connectivity across the entire disease spectrum in a manner that is considerably more difficult in nonlongitudinal studies of LOAD, given the uncertainty surrounding when and if sporadic subjects with MCI will develop AD.

The early decreases in DMN fcMRI in ADAD generally accord well with prior fcMRI studies in LOAD,2,4 in asymptomatic older individuals with biomarker evidence of Aβ deposition,19,20,36 and in asymptomatic APOE ε4 carriers.15,16,18 Additionally, the presence of observable changes in DMN fcMRI before symptom onset fits well with recent evidence that young, asymptomatic ADAD mutation carriers show changes in memory-task fMRI years before their estimated age of symptom onset.37 Although we did not directly compare ADAD with LOAD in our study, a subsequent analysis with the objective of comparing network disruption in ADAD and LOAD is presently in preparation by our colleagues at Washington University.38 That analysis includes fcMRI data from a subset of the DIAN subjects presented in this report, and uses a different analytic method to generate “seed-based” fcMRI network composite scores to compare ADAD subjects with a large LOAD cohort from Washington University. In contrast, we used ICA to identify whole-brain network maps of the DMN followed by region-of-interest analyses. By using this regional analytic approach, we were able to detect subtle regionally specific alterations in the DMN in presymptomatic mutation carriers. The ability to identify regionally specific changes in the DMN that occur early in the course of AD may be an important consideration for interpretation of data from upcoming secondary prevention clinical trials that plan to use DMN fcMRI as a secondary endpoint.

Lastly, our findings of decreased connectivity within specific regions of the DMN associated with increasing proximity to eYO and advancing CDR raise the intriguing question of how selective the pathobiologic process of AD is for the DMN, especially early in the course of the disease. Recent studies have elegantly demonstrated that other neurodegenerative diseases have distinctive patterns with which they affect distributed neural networks.39 The present findings of regional changes in DMN fcMRI early in ADAD, coupled with studies demonstrating that DMN is an early site for amyloid deposition14,36 and metabolic dysregulation in LOAD,14,40 suggest that specific regions within the DMN may be early, preferential targets of the AD pathophysiologic process. Multimodality imaging studies in ADAD, where AD pathology is relatively disentangled from the effects of advanced age and identification of those in the earliest stages of AD is more straightforward, may help us to understand the consequences of AD pathology on intrinsic functional networks and elucidate the neural basis for the complex cognitive and behavioral domains so adversely affected in AD.

Supplementary Material

Data Supplement:

ACKNOWLEDGMENT

The authors gratefully acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Additionally, the authors gratefully acknowledge the contributions of Drs. William Klunk, Chester Mathis, Michael Weiner, and Krista Moulder to the DIAN Imaging Core and data collection for this project. This manuscript has been reviewed by DIAN study investigators for scientific content and consistency of data interpretation with previous DIAN study publications.

GLOSSARY

amyloid-β
AD
Alzheimer disease
ADAD
autosomal dominant Alzheimer disease
ANOVA
analysis of variance
APP
amyloid precursor protein
CDR
Clinical Dementia Rating
DGC
DIAN Genetics Core
DIAN
Dominantly Inherited Alzheimer Network
DMN
default mode network
eYO
estimated years from expected symptom onset
fcMRI
functional connectivity MRI
GLM
general linear model
ICA
independent component analysis
LOAD
late-onset Alzheimer disease
LPC
left lateral parietal cortex
MCI
mild cognitive impairment
MNI
Montreal Neurological Institute
mPFC
medial prefrontal cortex
NCRAD
National Cell Repository for Alzheimer's Disease
PPC
precuneus/posterior cingulate
PSEN1
presenilin-1
PSEN2
presenilin-2
RPC
right lateral parietal cortex

Footnotes

Supplemental data at www.neurology.org

AUTHOR CONTRIBUTIONS

Drs. Chhatwal and Schultz: data analysis, writing of manuscript, statistical analysis and interpretation. Dr. Johnson: study design, study supervision, data analysis, writing of manuscript, statistical analysis and interpretation of results, critical revision of the manuscript for important intellectual content. Dr. Benzinger: study design, acquisition of data, critical revision of the manuscript for important intellectual content. Dr. Jack: study design, acquisition of data, critical revision of the manuscript for important intellectual content, interpretation of results. Dr. Ances: study design, acquisition of data, critical revision of the manuscript for important intellectual content. Ms. Sullivan: acquisition of data, critical revision of the manuscript for important intellectual content. Drs. Salloway, Ringman, Koeppe, Marcus, Thompson, Saykin, Correia, Schofield, Rowe, Fox, Brickman, Mayeux, McDade, Bateman, Fagan, Goate, Xiong, Buckles: study design, acquisition of data, critical revision of the manuscript for important intellectual content. Dr. Morris: study supervision, study design, critical revision of the manuscript for important intellectual content. Dr. Sperling: study design, study supervision, data analysis, writing of manuscript, statistical analysis and interpretation of results, critical revision of the manuscript for important intellectual content.

STUDY FUNDING

Data collection for this project was supported by the Dominantly Inherited Alzheimer Network (DIAN, U19AG032438 to J.C.M.) and data analyses by a K24 grant (AG035007 to R.A.S.), both funded by the National Institute on Aging (NIA).

DISCLOSURE

J. Chhatwal and A. Schultz report no disclosures. K. Johnson has served as paid consultant for Bayer, Bristol-Myers Squibb, GE Healthcare, Janssen Alzheimer's Immunotherapy, Siemens Medical Solutions, and Genzyme. He is a site coinvestigator for Lilly/Avid, Bristol-Myers Squibb, Pfizer, Janssen Immunotherapy, and Navidea. He has spoken at symposia sponsored by Janssen Alzheimer's Immunotherapy and Pfizer. T. Benzinger has served on an advisory board for Eli Lilly and has received research funding from Avid Radiopharmaceuticals. These relationships are not related to the content in the manuscript. C. Jack serves as a consultant for Janssen, Bristol-Myers Squibb, General Electric, Siemens, and Johnson & Johnson and is involved in clinical trials sponsored by Allon and Baxter, Inc. He receives research funding from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation. B. Ances and C. Sullivan report no disclosures. S. Salloway has received research support from Avid-Lilly, GE, Bayer, and Merck for studies related to amyloid imaging. He is a paid consultant to Lilly, GE, and Bayer. These relationships are not related to the content in the manuscript. J. Ringman receives research support from the NIA and the Jim Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarkers at UCLA, and has received compensation as an advisory board member for Takeda Pharmaceuticals and StemCells, Inc. These relationships are not related to the content of the manuscript. R. Koeppe reports no disclosures. D. Marcus is founder of Radiologics, Inc. This relationship is not related to the content of the manuscript. P. Thompson reports no disclosures. A. Saykin has received research support from Siemens Healthcare and Welch Allyn. He has served as a consultant to Eli Lilly and Siemens Healthcare in the past year. He serves as Editor-in-Chief of Brain Imaging and Behavior, a Springer journal. None of these relationships are relevant to the content in the manuscript. S. Correia reports no disclosures. P. Schofield has been a paid speaker for Janssen. This relationship is not related to the content in the manuscript. C. Rowe has been a consultant on brain PET imaging to GE Healthcare, Bayer, and Astra Zeneca, and received research grants from these companies and Avid Radiopharmaceuticals. These relationships are not related to the content of the manuscript. N. Fox reports that in the last 3 years his research group has received funding for image analysis services or consultancy from Bristol-Myers Squibb, Elan/Janssen, GE, Eli Lilly, Lundbeck, and Pfizer/Wyeth. These relationships are not related to the content in the manuscript. A. Brickman, R. Mayeux, and E. McDade report no disclosures. R. Bateman receives research support from the NIH, Alzheimer's Association, American Health Assistance Foundation, Ruth K. Broadman Biomedical Research Foundation, Anonymous Foundation, Eli Lilly research collaboration, Merck research collaboration, AstraZeneca research collaboration, and the DIAN Pharma Consortium: AIP, Biogen, Elan, Genentech, Lilly, Mithridion, Novartis, Pfizer, Roche, and Sanofi. He is a cofounder of C2N Diagnostics, and invited speaker at BMS, Lilly, Merck, Pfizer, Elan, Wyeth, Novartis, Abbott, Biogen, Takeda Foundation, and consulting relationships for the DZNE, Probiodrug AG, Medscape, En Vivo (SAB), and Merck. A. Fagan is a member of the Alzheimer's Disease CSF Biomarker Development Advisory Board for Roche and the US Alzheimer's Disease Advisory Board for Lilly USA. These relationships are not related to the content of the manuscript. A. Goate is a principal investigator on research grants from Pfizer, Genentech, and iPierian. She has served as a consultant for Finnogan, Henderson, Farabow, and Garret & Dunner, LLP. These relationships are not related to the content of the manuscript. C. Xiong has served as a paid consultant for Biogen-IDEC. This relationship is not related to the content in the manuscript. V. Buckles reports no disclosures. J. Morris has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies: Janssen Immunotherapy, Eli Lilly and Company, and Pfizer. He has served as a consultant for the following companies: Avid Radiopharmaceuticals, Eisai, Esteve, Janssen Alzheimer Immunotherapy Program, Glaxo-Smith-Kline, Novartis, Otsuka Pharmaceutical, and Pfizer. R. Sperling has served as a paid consultant for Bayer, Biogen-IDEC, Bristol-Myers Squibb, Eisai, Janssen Alzheimer Immunotherapy, Pfizer, Merck, and Roche, and as an unpaid consultant to Avid. She is a site coinvestigator for Avid, Bristol-Myers Squibb, Pfizer, and Janssen Alzheimer Immunotherapy clinical trials. She has spoken at symposia sponsored by Eli Lilly, Pfizer, and Janssen Alzheimer Immunotherapy. These relationships are not related to the content in the manuscript. Go to Neurology.org for full disclosures.

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