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Logo of neurologyNeurologyAmerican Academy of Neurology
 
Neurology. 2013 October 15; 81(16): 1425–1433.
PMCID: PMC3806583

The pattern of atrophy in familial Alzheimer disease

Volumetric MRI results from the DIAN study
David M. Cash, PhD,*

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Alzheimer's Association travel fellowship: Non profit, merit-based travel funding (airfare, hotel, conference registration) for attending AAIC 2012 conference for purposes of presenting

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. IXICO Ltd: Commercial (formal employer): Aug 2011-Feb 2012

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. Anonymous charitable foundation

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License fee payments, Technology or Inventions:

  1. (1) IXICO Ltd: CmicViewer software, License fee (2) Pathfinder Therapeutics: Image-guided liver surgery software, license fee Stock/Stock Options, Medical Equipment & Materials: IXICO Ltd: Stock options 2011

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
Gerard R. Ridgway, PhD,corresponding author*

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. University of Zurich, Honoraria and travel expenses for lectures (SPM courses)

Editorial Boards:

  1. NeuroImage, member of editorial board, 2011-2013

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. 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
Yuying Liang, MBBS,

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
Natalie S. Ryan, MBBS,

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
Kirsi M. Kinnunen, 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
Thomas Yeatman, MBBS,

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
Ian B. Malone, 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. Named researcher on UK Alzheimer's Society Grant RF116 (2013).

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
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 forQuintiles

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

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

Research Support, Government Entities:

  1. (1) 5P01AG026276 (PI: J. Morris)10/1/11-9/30/15NIH/NIAAdult Children Study (ACS)Role: Project 4 Principal Investigator (T. Benzinger)(2)1 U01AG032438 (PI: J. Morris)9/30/08-6/30/14NIH/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/NIAHASD: Healthy Aging and Senile Dementia, Imaging Core (Core Director, T. Benzinger)(4)1R01 NS066905-01 (PI: D. Marcus)9/30/09 - 6/30/2014NIH/NINDSBIRN Resources Facilitate the Personalization of MalignantBrain TumorRole: Co-Investigator(5)1R01 AG043434 (PI: C. Roe) 9/30/12-8/31/17NIHTitle: Driving Performance in Preclinical Alzheimer'sDisease Role: Co-investigator(6)1P01NS059560-01A1 (PI: A. Cross) 10/1/2008 - 7/31/12 NIH/NINDSTitle: Biomarkers and Pathogenesis of MS: From Mouse to HumanRole: Co-Investigator(7)Research Grant 6/01/10 - 6/31/12Washington University Institute of Clinical andTranslational Science,UL1 RR024992 Title: qBOLD MR measurements of oxygen extraction fraction in patients with brain tumorsRole: Project PI

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) National Multiple Sclerosis Society, Research Grant.

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) I have previously testified as a treating physician(not an expert witness).
Clifford R. 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. NONE

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

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 M. 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
Bernardino F. Ghetti, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. 1) Alzheimer disease transgenic mouse

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. 1) Bayer

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) NIA, PHS P30AG010133 2) NIA/NINDS PHS R13AG038256

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. 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
Andrew J. Saykin, PsyD,

Scientific Advisory Boards:

  1. (1) Commercial: Siemens Healthcare; Eli Lilly

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1) Commercial: Siemens Healthcare travel and speaker honoraria

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. (1) Commercial: (1) Baxter BioScience, (2) Bristol-Myers Squibb, (3) Eli Lilly, (4) Pfizer, Inc., (5) Siemens Healthcare; (2) Non-profit: (1) Dartmouth Medical School, (2) University of Michigan, (3) University of Vermont, (4) Vanderbilt University, (5) Brigham and Women's Hospital/Massachusetts General Hospital

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

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)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) Foundation for the NIH (FNIH): PI & co-PI of ADNI related genetics projects

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.
Colin L. Masters, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1) American Journal of Alzheimer's Disease and Other Dementias (1997 -), (2)Annals of Neurosciences (2009 -), (3)Archives of Neurology, International Advisory Committee (1996 -), (4)Brain Ageing (2002 -), (5)Current Alzheimer Research (2003 -), (6)Dementia and Geriatric Cognitive Disorders (1989 -), (7)International Journal of Biochemistry and Cell Biology (2006-), (8)Journal of Alzheimer's Disease (1997 -), (9)Journal of Clinical Neuroscience (1994 -), (10)Journal of Molecular Neurodegeneration (2005-), (11)Molecular Psychiatry (2011-), (12)Neurodegenerative Diseases (2002 -), (13)Neuropathology (1997 -), (14)Research and Perspectives in Alzheimer's Disease (Foundation IPSEN) (1990 -)

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. (1)Prana Biotechnology, (2)Eli Lilly Pty Ltd

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)NHMRC Program Grant, Reference 628946 Chief Investigator 2011-2015, (2) Dementia Collaborative Research Centre - Department of Health & Ageing. Principal Investigator. 2007-2013

Research Support, Academic Entities:

  1. (2)The Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) aims to improve understanding of the causes and diagnosis of Alzheimer's disease, and help develop preventative strategies. Chief Investigator . This program includes work in collaboration with CSIRO, Wyeth, Pfizer, GE, Astra Zeneca, Edith Cowan University, NARI, Austin Health. 2010-2014, (2)Dominantly Inherited Alzheimer Network (DIAN) study. DIAN is an international research partnership of leading scientists determined to understand a rare form of Alzheimer's disease that is caused by a gene mutation. Principal Investigator

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
John M. Ringman, MS, 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
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
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 #20821, (3) 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
Reisa A. Sperling, 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. Eisai, commercial entity Merck, commercial entity

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. National Institutes on Aging (NIA), K24

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
Nigel J. Cairns, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. I am on the editorial board of Acta Neuropathologica. I am on the editorial board of Brain Pathology.

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. Support for this work was provided by grants from the NIH (National Institute on Aging, P50-AG05681 and P01- AG03991), and the Charles Knight Fund.

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
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
Randall J. 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
John C. Morris, MD,

Scientific Advisory Boards:

  1. SABs for the following pharmaceutical and biotechnology companies in 2012-2013: Esteve; Janssen Alzheimer Immunotherapy Program; GlaxoSmithKline; 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,

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
Martin N. Rossor, MD, FRCP,

Scientific Advisory Boards:

  1. Martin Rossor receives consultancy fees as a member of the Safety Monitoring Committee for Servier. These are paid via UCL into departmental funds and not to Martin Rossor personally.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Editorial Board member of: Practical Neurology (1999 to date) Dementia and Geriatric Cognitive Disorders (2002-date) Neurodegenerative Diseases (2002 to date) Alzheimer's Research & Therapy (2010 to date) Faculty of 1000 2010 to date)

Patents:

  1. NONE

Publishing Royalties:

  1. Brain's Diseases of the Nervous System (11th edition), Oxford University press, 2001 Brain's Diseases of the Nervous System (12th edition), Oxford University Press, 2009 Dementia Blue Book Queen Square Textbook - royalties paid to hospital

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. Director NIHR Dementia and Neurodegenerative Diseases Clinical Research Network (DeNDRoN), 2005-2015 Director, NIHR Queen Square Dementia Biomedical Research Unit (2012-2015)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. As network co-ordinator of Alzheimer's Research Trust Co-ordinating Centre grant (1998-2010) As Principal Investigator of Alzheimer's Research Trust funded fellowship grant (2005-2010)

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
Sébastien Ourselin, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Although not receiving any compensation:Associate Editor, IEEE Transactions on Medical ImagingEditorial Board Medical, Medical Image Analysis

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Consulting for IXICO

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Siemens, General Electric, MIRADA Medical, IXICO, Medtronic

Research Support, Government Entities:

  1. EPSRC, MRC, Wellcome, Department of Health, NIHR

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 Nick C. Fox, MD, FRCP

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
, On behalf of the Dominantly Inherited Alzheimer Network (DIAN)

Abstract

Objective:

To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers.

Methods:

A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume.

Results:

Significant differences in gray matter (p < 0.05, family-wise error–corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers.

Conclusions:

Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.

Recent failures of phase III trials1,2 in Alzheimer disease (AD) have provoked concerns that the mild to moderate dementia stage may be too late for successful treatment.3,4 Arguably, an effective therapy should be applied at the earliest stages, to slow pathology accumulation and neurodegeneration before substantial irretrievable neuronal loss occurs. Consequently, researchers are designing prevention or secondary prevention studies.5,6 However, identifying and recruiting at-risk individuals from the general population requires extensive and costly screening, with uncertainty that participants will go on to develop AD. Alternatively, individuals carrying an autosomal dominantly inherited mutation for familial AD (FAD) could be targeted. While rare, hundreds of mutation-carrying families have been identified worldwide, with early and relatively predictable ages at onset. Effective therapeutic trials will require sensitive measures of early-stage disease progression, for which imaging shows great promise. Amyloid deposition is evident using PET at least a decade before symptomatic onset in FAD.79 Structural MRI reveals downstream consequences of neurodegeneration that appear closer to symptom onset. At diagnosis of AD dementia, hippocampi are 15% to 20% smaller than in age-matched controls,10 diverging from normal 3 to 5 years earlier.11 Some brain regions have produced conflicting results regarding the presence of an early increase in volume.9,1217

Importantly, virtually all previous studies considered a small sample (<25 participants) with a few FAD mutations. We report a voxel-based morphometry study on nearly 200 individuals from the international Dominantly Inherited Alzheimer Network (DIAN),9 which aims to understand the temporal ordering of abnormalities in FAD.

METHODS

Standard protocol approvals, registrations, and patient consents.

All aspects of the study were approved by the institutional review boards for each of the participating sites in DIAN. All participants provided written informed consent.

Participants.

All participants were recruited as part of the DIAN study, which aims to enroll up to 400 individuals at risk for one of the genetic mutations linked with FAD. Full details of participating sites, enrollment, and assessments in DIAN have been published.18 As part of obtaining the family history, a semistructured interview is conducted to determine the affected parent or sibling's age at onset. The estimated years to symptom onset (EYO) has been defined as the difference between this expected age at onset and the participant's current age; negative values indicate that an individual is younger than his or her expected age at onset. Genetic testing is performed to determine the presence of a mutation, but genetic data are provided only to those performing the analysis. This preserves patient confidentiality and ensures that both the participants and the clinicians assessing them remain blind to their genetic status.

At the time of analysis, 242 participants in the DIAN cohort were available from the third data cutoff (February 29, 2012). Of these, 192 had the complete genetic, demographic, and cognitive information required. Participants were divided into 3 groups based on the presence of a mutation and their Clinical Dementia Rating19 (CDR): 73 were noncarriers (NC); 69 carriers were classified as presymptomatic (pMut+) as their CDR was 0, indicating cognitive normality; and 50 carriers with a CDR of 0.5 or higher were defined as symptomatic (sMut+). Four NC had non-zero CDR, unlikely to be due to coincidental sporadic AD since they were all under 45 years of age, but perhaps arising from non-AD causes such as depression; these therefore formed a fourth group (symptomatic NC [sNC]) separate from the 69 asymptomatic NC (aNC).

MRI scanning.

Participants underwent volumetric T1-weighted MRI, using the accelerated sequence defined in the Alzheimer's Disease Neuroimaging Initiative second phase (ADNI-2).20 Individuals were scanned twice during a session, safeguarding against one poor-quality image. Sites used 3 different types of qualified 3-T scanner: Siemens Tim Trio, Siemens Verio, and Philips Achieva. Matching between scanners and image quality control were performed according to the ADNI protocol by the imaging core.21

Image analysis.

Voxel-based morphometry (VBM) was carried out using the SPM8 package (Statistical Parametric Mapping; http//www.fil.ion.ucl.ac.uk/spm) running on Matlab 7.12 (MathWorks; http://www.mathworks.com). Gray matter (GM) and white matter (WM) probability maps were obtained from the volumetric images using the tissue segmentation tools in the VBM8 toolbox (University of Jena; http://dbm.neuro.uni-jena.de) to obtain better segmentation of subcortical GM. One individual from the sMut+ group was excluded due to extensive WM pathology. Spatial normalization was performed using DARTEL,22 modulating normalized tissue maps to preserve their original volumes. Both scans from the imaging session were segmented, but only one from each individual was used in subsequent analysis (chosen as that with the higher SPM segmentation objective function). Images were smoothed using a Gaussian kernel with 6 mm full-width at half-maximum, balancing the detection of small-scale anatomical differences while ameliorating misalignment. GM and WM analysis masks were created by averaging individual smoothed normalized GM and WM segmentations and dichotomizing at a value of 0.2.23

Data were fitted with a general linear model (GLM) in SPM8, containing the following terms: a 4-level group factor (aNC, sNC, pMut+, sMut+); a 10-level factor representing the acquisition sites; a 2-level factor indicating the presence of an APOE ε4 allele (a well-established risk factor for sporadic AD24,25); a factor for gender; a covariate for total intracranial volume (TIV); and a covariate for EYO interacting with the group factor. TIV was calculated by summing GM, WM, and CSF volumes from the VBM8 segmentation. Because multiple participants from the same families enrolled in DIAN, family membership was modeled as a random effect, permitting covariance among relatives. Contrasts of the GLM parameters were used to test for differences among the 3 main diagnostic groups (aNC, pMut+, and sMut+) and among the 10 sites (F contrasts with 2 and 9 numerator degrees of freedom, respectively). Contrasts were also used to detect pairwise differences between diagnostic groups or changes due to APOE status (one-tailed t contrasts). Multiple comparison correction was performed to control voxel-level family-wise error (FWE) at p < 0.05, though some results are shown at an uncorrected level of p < 0.001 (in some cases alongside unthresholded effect maps) to provide better characterization of patterns not reaching significance.

Forthcoming clinical trials may recruit mutation carriers either with mild symptoms or near to their expected onset. Therefore, we performed additional analyses where the carrier groups were divided into smaller subgroups according to criteria relevant for clinical trials. The sMut+ group was divided according to clinical severity as assessed by CDR: 31 individuals with CDR = 0.5 and 19 with CDR > 0.5. The pMut+ group was divided into 3 subgroups based on EYO: 30 individuals more than 15 years away, 24 between 15 and 6 years away, and 15 less than 6 years from expected onset. As the EYO variable defined these subgroups, the EYO group interaction was replaced with a simple age covariate in this analysis.

RESULTS

Demographics of included participants are summarized in table 1. On average, the presymptomatic carriers (pMut+) were more than 10 years away from their expected symptom onset; 80% of carriers have a mutation in the presenilin-1 gene (PSEN1), 8% presenilin-2 (PSEN2), and 12% amyloid precursor protein (APP).

Table 1
Demographics of DIAN participants used in this study

Figure 1 shows the F test (p < 0.05, FWE corrected) for significant GM differences among the 3 groups of interest: the GM volumes were lower in carriers in 1) the temporal lobe, both medially in the region of the hippocampi and laterally in the temporal neocortex; 2) precuneus; 3) cingulate gyrus, primarily in the posterior region; 4) putamen; and 5) thalamus. For each of these regions, figure 1 provides an illustrative (though circular26) plot of the linear fit of GM volume to EYO at the voxel with the peak F test statistic. A similar F test for WM differences is shown in figure 2. There were significant reductions in the fornix and cingulum, projections to the hippocampus, precuneus, and posterior cingulate. Table e-1 on the Neurology® Web site at www.neurology.org details these GM and WM findings. When examining the pairwise comparisons, the t test for GM decrease between aNC and sMut+ (figure e-1) looks similar to the overall group test. No findings survived FWE correction when comparing aNC and pMut+.

Figure 1
Significant group differences in gray matter volume
Figure 2
Significant group differences in white matter volume

We performed reverse contrasts to test for GM and WM increases between NC and carriers. For sMut+, there was one area of significantly increased GM on the boundary between the splenium of the corpus callosum and the lateral ventricle. There were 2 findings for WM: the inferior boundary of the caudate and the inferior boundary of the accumbens/putamen. There were no significant increases between aNC and pMut+.

Figure 3 provides GM results when the symptomatic carrier group is subdivided according to CDR. Findings of decreased GM are present even in the mildest symptomatic subgroup (CDR = 0.5). Differences are more widespread in the CDR > 0.5 subgroup despite the smaller sample size. When directly comparing these 2 subgroups, there are significant findings of decreased GM in the more affected (CDR > 0.5) subgroup within the medial temporal lobe and posterior cingulate.

Figure 3
Gray matter differences in symptomatic carriers subgrouped by clinical dementia rating

No findings survived FWE correction when comparing EYO-stratified presymptomatic carriers to NC, but there were trends for carriers to show lower GM volume nearer to their expected age at onset. Figure 4 illustrates this trend and provides the effect maps from each EYO subgroup vs NC. In the subgroup less than 5 years away from onset, there is a suggestion of reduced GM in the thalamic areas, and in neocortical areas of the lateral temporal lobe.

Figure 4
Effect maps for subgroups of asymptomatic carriers according to estimated years to symptom onset

DISCUSSION

VBM was performed on volumetric MRI from a large cohort of individuals at risk for, or mildly affected by, autosomal dominantly inherited AD from the DIAN study; 192 individuals were studied—a much larger sample than prior FAD studies. The larger sample size in this study can provide a consensus pattern of atrophy, whereas single site studies have provided variable results, likely due to unique patterns of atrophy in the smaller cohorts of mutations and families. We were careful in attempting to account for heterogeneity due to multiple sites and scanners: there were significant effects of site in the peripheral areas of the brain and near the thalamus for GM and in the inferior frontal lobe near the frontal pole for WM (figure e-2), but no significant site-by-group interaction. These findings are mainly in areas frequently affected by differences in hardware and susceptibility artifacts. The site effects show little similarity to the main results, but nevertheless demonstrate the importance of modeling this factor.

We found evidence of GM reduction in 3 areas that are well-recognized in the sporadic (late-onset) AD literature: the temporal lobe, precuneus, and cingulate. There were also signs of early change in the putamen and thalamus—structures not typically associated with sporadic AD, though such an association is documented when comparing patients with AD with elderly subjects who have no objective memory decline.27,28 In this study, we observed differences in these structures at earlier stages of the disease, with carriers at CDR = 0.5. Recently, decreased volumes and increased fractional anisotropy (FA) of the thalamus and caudate were reported in presymptomatic PSEN1 mutation carriers29 (11 participants in that study were also included the current work, though not using the same volumetric T1 scans). These results are interesting in light of amyloid PET studies of FAD that report increased uptake in these areas, which might be the earliest regions of amyloid deposition for some individuals. Striatal uptake of Pittsburgh compound B (PiB) was reported for 5 asymptomatic and 5 symptomatic carriers with 2 PSEN1 mutations8; uptake in cortical areas was also increased compared to controls, though not as much as in sporadic late-onset AD. A similar study of 7 asymptomatic and symptomatic patients with 3 different PSEN1 mutations found that striatal PiB uptake was not increased compared to sporadic AD, but uptake was increased in the thalamus.7 However, it remains an open question whether the presence of amyloid alone directly causes atrophy, or whether it is a downstream effect mediated by tau or requiring some other mechanism.3032

WM was reduced in both input (cingulum) and output (fornix) connections to the hippocampi. This is consistent with reported decreases in cross-sectional area and FA of the fornix columns in FAD mutation carriers.33 We also observed WM differences in areas close to the posterior cingulate and precuneus. However, caution should be exercised when interpreting WM alterations identified using VBM. T1-weighted images provide little anatomical information about WM tracts, so spatial normalization is driven by matching detailed convolutions in GM and the ventricular boundary. Partial volume effects, especially in the small medial temporal structures, could also affect the findings. As most of the WM changes overlap areas that predominantly contain GM, these results may reflect GM atrophy rather than actual WM differences. Future studies using tensor-based morphometry or diffusion-weighted imaging should provide a more complete picture of the WM alterations in FAD.

The majority of the differences observed in this study were in symptomatic mutation carriers. Most of these carriers have a CDR of only 0.5, which usually indicates mild symptoms, insufficient to interfere severely with everyday activities. GM volume reduction was still detectable when the symptomatic carriers with CDR greater than 0.5 were excluded. This suggests that the results were not being driven by the smaller number of more affected individuals, but that changes are already occurring at the time of the first signs of cognitive impairment in FAD. This group is also likely to have a more homogenous pathology than analogous groups in the sporadic AD cohorts.

No significant findings of either increased or decreased GM were present in the presymptomatic carrier group, though a trend toward progressive atrophy was suggested by the effect maps of the EYO-based subgroups. Another suggestion of increasing atrophy near to onset is observed when plotting the linear fit of the GM volumes with respect to EYO, shown for key areas in figure 1. Given reports that presymptomatic FAD may feature increased GM volume,13,14 we also looked at reverse contrasts for areas of increased GM; no findings survived FWE correction. Findings of increased volume may be related to specific mutations and are likely to be subtle in comparison to decreases caused by neurodegeneration, requiring more sensitive measures to identify them. In the symptomatic mutation group, there were some findings of increased volume relative to NC, but given the locations (splenium for GM, caudate and accumbens for WM) and low tissue probabilities, these may reflect partial volume effects.

The earliest point at which GM changes can be observed presymptomatically still needs to be determined. Two structural MRI studies have been performed on the PSEN1 E280A Colombian kindred to identify changes in presymptomatic carriers compared to age-matched controls. One study17 using VBM on very young carriers—approximately 20 to 25 years from expected age at onset—found an area of GM decrease in the parietal lobe, which survived correction for multiple comparisons only when using a smaller search volume based on findings for patients with sporadic AD. The other study15 used carriers much closer (~6 years) to expected onset and observed changes in cortical thickness of the precuneus, angular gyrus, and superior parietal lobule. In a similar sized cohort (25 carriers, 10 NC),14 there was evidence of GM volume loss in the thalamus and putamen for 9 carriers with CDR of 0, who were on average 15 years before their family's median age at diagnosis. It is not clear how this relates to the time of earliest symptoms, as more than half reported subjective memory complaints.

Our results indicate that widespread GM differences might only occur relatively close to the onset of symptoms. In the at-risk group that we studied, there were only 15 presymptomatic carriers within 5 years of expected age at onset. Having only a small sample in this crucial risk window limits the power to detect changes. VBM is also often less sensitive than targeted volumetric measurements of key structures. Hippocampal volume reductions have been observed as early as 10 years before expected onset in the DIAN cohort.9 This finding of earlier change could be due to methodologic differences (specifically measuring hippocampal volume as opposed to VBM with correction for multiple comparisons); in addition, the finding may have been partially driven by affected carriers who were younger than their expected age at onset. We plan to use the results from this VBM analysis to determine which structures would be of interest for subsequent volumetric analyses.

Furthermore, estimated onset will be inaccurate, due to both true variability in the age at onset over generations and imprecision in determining parental onset. Studies that have information on individuals' actual clinical onsets (i.e., longitudinal studies tracking mutation carriers from presymptomatic to symptomatic stages) are likely to have greater precision in defining the location and timing of losses. Importantly, as part of the DIAN study, the participants studied here will have continued follow-up assessments, including imaging. We expect these longitudinal assessments to enable more sensitive measurement of location, timing, and rate of change in the presymptomatic stages.

In light of previous observations regarding possible clinical,34 imaging,35 molecular,36,37 and neuropathologic differences between individuals with APP and PSEN1 mutations, and among individuals with distinct PSEN1 mutations,38 atrophy patterns may differ among these subgroups. Since this study predominantly contains PSEN1 mutation carriers, it is difficult to determine what differences might be present in FAD caused by APP, PSEN1, or PSEN2 mutations. As more participants enroll, it will become clearer whether there are indeed differences in the atrophy patterns among these 3 genes (or even among the more common specific point mutations within these genes). There were no significant findings related to carrying an APOE ε4 allele, which could be due to a difference in the roles that the APOE gene plays in familial and sporadic AD.

Brain-wide analysis using VBM indicates that individuals with FAD, even when showing the earliest of symptoms, already have significantly less GM in brain areas previously linked to AD, but there also appear to be losses in the putamen and thalamus. This is consistent with prior reports of amyloid deposition in these structures in FAD. These results provide further insight into the pattern of atrophy in FAD, which may help to inform decisions regarding volumetric MRI biomarkers for clinical trials.

Supplementary Material

Data Supplement:
Coinvestigators:

ACKNOWLEDGMENT

This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. They thank the participants and their families and the DIAN research and support staff at each of the participating sites for their contributions to this study (http://www.dian-info.org/personnel.htm).

GLOSSARY

AD
Alzheimer disease
ADNI
Alzheimer's Disease Neuroimaging Initiative
aNC
asymptomatic noncarriers
CDR
Clinical Dementia Rating
DIAN
Dominantly Inherited Alzheimer Network
EYO
estimated years to symptom onset
FA
fractional anisotropy
FAD
familial Alzheimer disease
FWE
family-wise error
GLM
general linear model
GM
gray matter
NC
noncarriers
PiB
Pittsburgh compound B
pMut+
presymptomatic carriers
sMut+
symptomatic carriers
sNC
symptomatic noncarriers
TIV
total intracranial volume
VBM
voxel-based morphometry
WM
white matter

Footnotes

Supplemental data at www.neurology.org

AUTHOR CONTRIBUTIONS

Dr. Cash performed the analysis and wrote the manuscript. Dr. Ridgway performed the analysis and wrote the manuscript. Dr. Liang interacted with the patients and collected data at the London DIAN site, as well as assisting with preparation of the manuscript. Dr. Ryan interacted with the patients and collected data at the London DIAN site, as well as assisting with preparation of the manuscript. Dr. Kinnunen assisted in the imaging analysis and preparation of the manuscript. Dr. Yeatmann assisted in the imaging analysis and preparation of the manuscript. Dr. Malone assisted in the imaging analysis and preparation of the manuscript. Dr. Benzinger provided central support as DIAN imaging core leader and assisted in the preparation of the manuscript. Dr. Jack supervised quality checking of all volumetric T1 data and assisted in the preparation of the manuscript. Dr. Thompson was part of the DIAN imaging core and assisted in the preparation of the manuscript. Dr. Ghetti is the primary investigator at the DIAN IUPUI site and assisted in the preparation of the manuscript. Dr. Saykin is the imaging lead at the DIAN IUPUI site and assisted in the preparation of the manuscript. Dr. Masters is the primary investigator at the DIAN University of Melbourne site and assisted in the preparation of the manuscript. Dr. Ringman is the primary investigator at the DIAN UCLA site and assisted in the preparation of the manuscript. Dr. Salloway is the primary investigator at the DIAN Brown/Butler's site and assisted in the preparation of the manuscript. Dr. Schofield is the primary investigator at the DIAN Neuroscience Research Australia site and assisted in the preparation of the manuscript. Dr. Sperling is the primary investigator at the DIAN Brigham and Women's Hospital site and assisted in the preparation of the manuscript. Dr. Cairns provided central support as the DIAN neuropathology core leader and assisted in the preparation of the manuscript. Dr. Marcus provided central support as the DIAN informatics core leader and assisted in the preparation of the manuscript. Dr. Xiong provided central support as the DIAN biostatistics core leader and assisted in the preparation of the manuscript. Dr. Bateman provided central support as the DIAN clinical core leader and assisted in the preparation of the manuscript. Dr. Morris provided central support as the DIAN chief investigator and assisted in the preparation of the manuscript. Dr. Rossor is the primary investigator at the DIAN UCL site and supervised the design and the preparation of the manuscript. Dr. Ourselin supervised the analysis, the design, and the preparation of the manuscript. Dr. Fox supervised the analysis, the design, and the preparation of the manuscript.

STUDY FUNDING

Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer's Network (DIAN, U01AG032438; J.C. Morris, principal investigator) funded by the National Institute on Aging (NIA). Work at UCL was supported by the NIHR Queen Square Dementia BRU. Drs. Cash and Kinnunen are supported by a grant from an anonymous charitable foundation. Drs. Ridgway and Ryan and Professor Fox are supported by the Medical Research Council (grant numbers MR/J014257/1, G0900421, G116/143). Professors Fox and Rossor are NIHR senior investigators. The Dementia Research Centre is an Alzheimer's Research UK Co-ordinating Centre and has also received equipment funded by Alzheimer's Research UK and Brain Research Trust. The Wellcome Trust Centre for Neuroimaging is supported by core funding from the Wellcome Trust (grant number 091593/Z/10/Z).

DISCLOSURE

D. Cash reports no disclosures. G. Ridgway has received honoraria for teaching on SPM courses. Y. Liang, N. Ryan, K. Kinnunen, T. Yeatmann, and I. Malone report no disclosures. T. Benzinger has received personal compensation for activities with Eli Lilly & Company as an advisory board participant and has received research support from Avid Radiopharmaceuticals. C. Jack has received personal compensation for activities with Janssen, Eisai Inc., General Electric, Johnson & Johnson, and Eli Lilly & Company and has received research support from Pfizer Inc., Allon, and Baxter. P. Thompson reports no disclosures. B. Ghetti has received personal compensation for activities with Bayer Pharmaceuticals Corporation and has received research support from the NIA. A. Saykin and C. Masters report no disclosures. J. Ringman has received personal compensation for activities with Takeda Pharmaceuticals and StemCells, Inc. as an advisory board member. Dr. Ringman has received research support from Janssen, Pfizer Inc., Accera, Bristol-Myers Squibb, Inc., and Wyeth Pharmaceuticals. S.P. Salloway reports that he has received support to his hospital for conduct of clinical trials from NIA-ADNI, NIA-DIAN, Alzheimer's Association-DIAN Clinical Trials, Avid Radiopharmaceuticals, Janssen Alzheimer's Immunotherapy, Baxter, BMS, Pfizer, Genentech, GE Healthcare, Roche, Merck, and Biogen. He has served as a consultant for Baxter, Pfizer, Athena, BMS, Merck, Lilly, Roche, GE Healthcare, and Janssen Alzheimer Immunotherapy. P. Schofield reports that his research is supported by NIH (DIAN) and the Wicking Trust for this project. Other grant support comes from the Australian National Health and Medical Research Council, the Australian Research Council, and beyondblue. He has received a speaker fee from Janssen Pharmaceuticals unrelated to this work. R. Sperling has served as a consultant (without personal compensation) for Eli Lilly, Janssen, Avid, and Roche, and as a paid consultant for Merck, Eisai, and Satori. She has received research support from Janssen, Pfizer, Avid, the Alzheimer's Association, American Health Assistance Foundation, Fidelity Biosciences, and the National Institute on Aging. N. Cairns, D. Marcus, and C. Xiong report no disclosures. R. Bateman has received personal compensation for activities with Link Medicine, JAI, Bristol-Myers Squibb Company, Pfizer Inc., Merck, SPRI, Elan Corporation, Eisai Inc., and Medtronic, Inc., received royalty payments from Washington University, and received research support from AstraZeneca Pharmaceuticals and Merck & Co., Inc. He has received personal compensation in an editorial capacity for serving as Associate Editor, Journal of Neuropsychiatry and Clinical Neurosciences. J. Morris has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies: Janssen Immunotherapy and Pfizer. Dr. Morris has served as a consultant for the following companies: Eisai, Esteve, Janssen Alzheimer Immunotherapy Program, GlaxoSmithKline, Novartis, and Pfizer. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants P50AG005681, P01AG003991, P01AG026276, and U19AG032438. M. Rossor reports no disclosures. S. Ourselin has received personal compensation for activities and research support from IXICO Ltd. He also received financial support for his research from Siemens Molecular Imaging, MIRADA Medical Solution, and General Electric Healthcare. N. Fox reports that his research has received payment for consultancy or for image analysis services from Avid/Lilly, BMS, Elan/Janssen, GE, Lundbeck, and Pfizer/Wyeth. Go to Neurology.org for full disclosures.

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