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Logo of neurologyNeurologyAmerican Academy of Neurology
 
Neurology. 2013 July 30; 81(5): 487–500.
PMCID: PMC3776529

Imaging markers for Alzheimer disease

Which vs how
Giovanni B. Frisoni, MD,corresponding author

Scientific Advisory Boards:

  1. LUNDBECK, COMMERCIAL

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1)Lilly, (2)Bayer, (3)Lundbeck, (4)Elan, (5)Astra Zeneca, (6)Pfizer

Editorial Boards:

  1. (1)Lancet Neurology, Member of the editorial board , (2)Aging Clinical & Experimental Research, Member of the editorial board (3)Alzheimer's Diseases & Associated Disorders (4)Neurodegenerative Diseases, Member of the editorial board. (5)Neurobiology of Aging, Imaging Section Editor

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. IRCCS Fatebenefratelli, Brescia, Italy

Consultancies:

  1. (1) IRCCS SDN Naples, non profit (2) Taurx, commercial

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1)Wyeth Int.l, (2)Lilly Int.l, (3)Lundbeck Italia

Research Support, Government Entities:

  1. NONE

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
Martina Bocchetta, MS,

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
Gael Chételat, 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
Gil D. Rabinovici, MD,

Scientific Advisory Boards:

  1. (1) Scientific Advisory Board for Novartis Vaccines and Diagnostics;

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Speaking honoraria from UCSD,City College of San Francisco

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Eli Lilly

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Avid Radiopharmaceuticals/Eli Lilly

Research Support, Government Entities:

  1. (1) NIH/NIA, K23-AG031861, PI, 2008-2013

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) Alzheimer's Association, (2) John Douglas French Alzheimer's Foundation, (3) Hellman Family 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
Mony J. de Leon, EdD,

Scientific Advisory Boards:

  1. Non-profit French Alzheimer Foundation DZNE German Alzheimer Inititive

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Non-profit Nature Medicine travel Roche Pharma SAB participation Vayacog SAB participation

Editorial Boards:

  1. NONE

Patents:

  1. Image analysis patents managed by NYU and licensed to Abient

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 RO1 grant support

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
Jeffrey Kaye, MD,

Scientific Advisory Boards:

  1. (1) Eli Lily data safety monitoring board for Alzheimer's drug (2011- 12) (2) Janssen Research Advisory Committee (2012)

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Frontiers of Aging Neuroscience, Associate Editor (2010-2013) Alzheimer and Dementia, Editorial Advisory Board (2005-2013)

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. The NIA funded Oregon Alzheimer's Disease Center is an NIA- funded Alzheimer's Disease Neuroimaging Initiative (ADNI) site. As part of this activity we perform MRI and PET scans on ADNI research volunteers on a regular basis. There are about 30 volunteers or patients enrolled in our center at any given time under this program. I receive .01% effort from this grant.

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Funded for research by the Department of Veteran's Affairs by a Merit Review grant, and National Institutes of Health (NIH) grants # P30AG024978, R01AG024059 (2007-2012), P30 AG008017. All as PI; all current except as noted.

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Robert Wood Johnson Foundation (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
Eric M. Reiman, MD,

Scientific Advisory Boards:

  1. AstraZeneca Bayer Eisai Elan Eli Lilly GlaxoSmithKline Intellect Novartis Siemens Takeda

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Deputy Editor, Journal of Clinical Psychiatry

Patents:

  1. Patent pending: biomarker strategy to evaluate preclinical AD treatments (through Banner Health)

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. AstraZeneca Avid/Eli Lilly Genentech

Research Support, Government Entities:

  1. NIA (R01 AG031581, PI) NIA (P30 AG19610, PI) NIA (RF1 AG041705, PI) State of Arizona (Arizona Alzheimer's Consortium, PI)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Banner Alzheimer's Foundation Anonymous Foundation Nomis 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
Philip Scheltens, MD, PhD,

Scientific Advisory Boards:

  1. Advisory boards of: Danone Research, BMS, Genentech, Pfizer, GE healthcare, Jansen AI, Lilly, Merck

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Lundbeck, educational symposium, 2009, 2012 Nutricia, CTAD 2011 and AAIC 2012 Jansen AI, EFNS 2012

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Pfizer, GE Healthcare, AVID/Lilly, genentech, Jansen AI, Danone.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. GE Healthcare

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Alzheimer Nederland; sponsor Alzheimer Center, from 2000 onwards Stichting VUmc fonds: sponsor Alzheimer Center from 2005 onwards Innovation Fund: sponsor of Center 2009-2014

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
Frederik Barkhof, MD, PhD,

Scientific Advisory Boards:

  1. Scientific consultant to Bayer-Schering, Sanofi- Aventis, Synthon, Novartis, Biogen-Idec, Merck-Serono, GE medical systems, Roche, Janssen, TEVA

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Editorial board member for Brain, Eur Radiol, J Neurol, Neuroradiology, Radiology

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Consultant for Sanofi-Aventis, Synthon, Janssen, Novartis, Biogen-Idec, GE medical systems, Roche

Speakers' Bureaus:

  1. Serono Symposia speaker , 2010 and 2011 Novartis symposium speaker 2009, 2010 and 2011 BioClinica symposium speaker 2010 Bayer-Schering symposium speaker 2010 Medscape CME speaker 2011 and 2012

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Neugrid4you (FP7 european committee)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Dutch foundation for MS Research - centre grant 2010-2014

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
Sandra E. Black, MD,

Scientific Advisory Boards:

  1. (1) Pfizer DSMB (2) National Institutes of Health (NIH)/University of California – Executive and Steering Committee ofAlzheimer's Disease Neuroimaging Initiative(ADNI) (3) Canadian Institutes of Health Research (CIHR) – Canadian Atherosclerosis Imaging Network (CAIN) and Medical Imaging Trials Network of Canada (MITNEC) Steering Committee

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1) Alzheimer's Research & Therapy, editorial board member, 2010- (2) Brain and Behavior, editorial board member, 2011- (3) Chinese Journal of Geriatrics, international editorial board member, 2011-

Patents:

  1. (1) INCAS (Integrated NeuroCognitive Assessment System) - Cognitive Assessment Tool and Method 2) This patent pending proposes a tablet-based computerized cognitive assessment tool integrated into a electronic patient record that can be accessed by healthcare professionals involved in a patient's circle of care and at the same time can generate a letter to the referring physician and standardized core data elements that can be used for research purposes wiht proper consent. This was initially piloted for patients with stroke and patients with dementia. If this is successful, any earnings will go to my institution.

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. 1) Novartis ad hoc consulting 2) Pfizer ad hoc consulting 3) Roche ad hoc consulting 4) Elan Pharmaceutical ad hoc consulting 5) Bristol Meyer Squibb ad hoc consulting 6) Glaxo Smith Kline 7) GE Healthcare

Speakers' Bureaus:

  1. 1)Pfizer 2)Eisai 3)Novartis

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Roche (2) GlaxoSmithKline Inc. (3) Pfizer Canada Inc. (4) Novartis This support goes to my institution, not to me personally.

Research Support, Government Entities:

  1. (1) CIHR, MOP-106485, Principal Investigator (PI), 2010- 2013 (2) CIHR, MT-13129, PI, 2008-2013 (3) CIHR, MOP-82744, Co-PI, 2007-2012 (4) National Institutes of Health (NIH), R01 NS057514, Co-PI, 2007-2010 (5) NIH, U01 AG24904 (ADNI), Site PI, 2005-2013 (7) Canada Foundation for Innovation (CFI), CAIN, Site Co-PI, 2009-2014 (8) CIHR, CAIN, Site Co-PI, 2008-2013

Research Support, Academic Entities:

  1. (1) Brill Chair in Neurology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre (2) Sunnybrook Research Institute (3) Department of Medicine, Sunnybrook Health Sciences Centre (4)Faculty of Medicine and Department of Medicine, University of Toronto

Research Support, Foundations and Societies:

  1. (1) Canadian Stroke Network (CSN), Co-PI, 2009-2011 (2) Heart and Stroke Foundation of Ontario (HSFO), T 6075, Co-PI, 2007-2012 (3) HSFO, T 6383, Co-PI, 2008-2011

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
David J. Brooks, MD,

Scientific Advisory Boards:

  1. Austrian KLIF GlaxoSmithKline UCB

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. GE Healthcare

Editorial Boards:

  1. Associate Editor of Brain

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. GE Healthcare Shire Pharmaceuticals Acadia

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. UK Medical Research Council UK 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
Maria C. Carrillo, MD, PhD,

Scientific Advisory Boards:

  1. Non-Profit - Alzheimer's Association MSAC Commercial - Genworth Insurance

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
Nick C. Fox, MD, PhD,

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
Karl Herholz, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Journal of Nuclear Medicine, editorial board European Journal of Nuclear Medicine and Molecular Imaging, editorial board PlosONE, academic editor Neurotherapeutics, editorial board

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. GE-Healthcare DZNE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. AVID radiopharmaceuticals

Research Support, Government Entities:

  1. European Commission, Framework 7, INMIND, EMIF-AD

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
Agneta Nordberg, MD, PhD,

Scientific Advisory Boards:

  1. Elan Merck GE Healthcare Lundbeck AB Pfizer Avid Johnson and Johnson

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Novartis Merz Bayer Pfizer JansenCilag En Vivo GE Healthcare

Editorial Boards:

  1. Journal Alzheimer Research advisory board memember Alzheimer Disease and Therapy advisory board member Current Alzheimer Research advisory board member

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. GE Healthcare Bayer Health

Research Support, Government Entities:

  1. Swedish Research Council (project 05817), Karolinska institutet Neurostrategic program, EU 7th Program INMIND, Swedish Brain Power

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Knut and Alice Wallenberg foundation Swedish Brain Power KI Strategic Neuroscience program Swedish Brain foundation Swedish Alzheimer foundation Stohnes foundation EU Inmind

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 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. 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
William J. Jagust, MD,

Scientific Advisory Boards:

  1. Genentech 2009, 2011, 2013

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Associate Editor, Frontiers in Human Neuroscience (current). Editorial Board Annals of Neurology, Brain Imaging and Behavior. Alzheimer's Disease and Associated Disorders, Neuroimage: Clinical (current)

Patents:

  1. NONE

Publishing Royalties:

  1. Imaging the Aging Brain, Oxford University Press 2009, Jagust and D'Esposito, eds

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Consultant Synarc 2008, 2009, 2010, 2011, 2012, 2013 Consultant Elan/Janssen Alzheimer Immunotherapy 2008, 2009, 2010, 2011 Consultant Siemens Medical 2012 Consultant Genentech 2009, 2011, 2013 Consultant Abbott Pharmaceuticals 2010 Consultant GE Healthcare 2010 Consultant Bayer Healthcare 2010 Consultant TauRx 2010, 2011 Consultant Otsuka Pharmaceuticals 2010

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, Principal Investigator on the following grants: AG034570 AG027859 AG027984 Alzheimer's Association ZEN-08-87090 NIH Co-Investigator on the following grants: AG036535 AG032306 AG031563 AG030048 AG024904

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Alzheimer's Association 2008-2011

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
Keith A. Johnson, MD, PhD,

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

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE
Christopher C. Rowe, MD, PhD,

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

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  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

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE
Reisa A. Sperling, MD,

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

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE
William Thies, PhD,

Scientific Advisory Boards:

  1. I am an employee of the Alzheimers Association National office in Chicago Illinois.

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

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  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE
Lars-Olof Wahlund, MD, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

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  1. NONE

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  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

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  1. NONE
Michael W. Weiner, MD,

Scientific Advisory Boards:

  1. VACO,Pfizer, BOLT Inter-national

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. University of California, Los Angeles, CTAD (Clinical Trials on Alzheimer's Disease)ANT Congres, Pfizer, AD PD meeting, Paul Sabatier University, Novartis, Tohoku University, MCI Group, France, Travel eDreams, Inc., Neuroscience School of Advanced Studies (NSAS, Danone Trading, BV

Editorial Boards:

  1. Alzheimer's & Dementia Editorial Board, MRI Editorial Board

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. University of California, San Francisco; San Francisco VA Medical Center

Consultancies:

  1. Pfizer,Janssen, KLJ Associates, Easton Associates, Harvard University,inThought, INC Research, Inc., University of California, Los Angeles (UCLA, Alzheimer's Drug Discovery Foundation (ADDF)

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Merck, Avid

Research Support, Government Entities:

  1. NIH, DOD, VA Stock/Stock Options, Medical Equipment & Materials: Synarc, Elan

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

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  1. NONE
Patrizio Pasqualetti, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Epidemiology, Biostatistics and Public Health, Consulting Editor,2012-2013

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

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE
and Charles DeCarli, MD

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Multiple honoraria for invited speaking engagements at various universities.

Editorial Boards:

  1. Alzheimer Disease and Associated Disorders, an international journal, Editor-in-Chief, 2006--present

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Avid Pharmaceuticals, consulting

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. Multiple R01s, a P30 and through the NIH

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

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  1. NONE

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  1. NONE

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From the LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine) (G.B.F., M.B.), IRCCS, S. Giovanni di Dio, Fatebenefratelli Brescia, Italy; INSERM (G.C.), U1077, Caen; Université de Caen Basse-Normandie (G.C.), UMR-S1077, Caen; Ecole Pratique des Hautes Etudes (G.C.), UMR-S1077, Caen; CHU de Caen (G.C.), U1077, Caen, France; Memory and Aging Center, Department of Neurology (G.D.R.), University of California, San Francisco (C.D., M.W.W.); New York University School of Medicine (M.J.d.L.), Center for Brain Health, New York, NY; Oregon Health & Science University (J.K.), Portland; the Portland Veterans Affairs Medical Center (J.K.); Banner Alzheimer's Institute (E.M.R.), Phoenix, AZ; Department of Neurology and Alzheimer Center (P.S.), and Departments of Radiology and Nuclear Medicine (F.B.), VU University Medical Center, Amsterdam; the Netherlands; Department of Medicine (Neurology) (S.E.B.), University of Toronto, Sunnybrook Research Institute, Toronto, Canada; Division of Brain Sciences (D.J.B.), Faculty of Medicine, Imperial College, London, UK; Aarhus University (D.J.B.), Denmark; Medical & Scientific Relations (M.C.C., W.T.), Alzheimer's Association, Chicago, IL; University College London Institute of Neurology (N.C.F.), London; Wolfson Molecular Imaging Centre (K.H.), Institute of Brain, Behaviour and Mental Health, University of Manchester, UK; Karolinska Institutet (A.N.), Karolinska University Hospital Huddinge, Stockholm, Sweden; Alzheimer Neurobiology Center (A.N.), Karolinska Institutet, Stockholm; Department of Diagnostic Radiology (C.R.J.), Mayo Clinic and Foundation, Rochester, MN; School of Public Health & Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; Department of Neurology (K.A.J., R.A.J.), Massachusetts General Hospital and Brigham and Women's Hospital, Boston; Department of Nuclear Medicine (C.C.R.), Centre for PET, Austin Health, Melbourne, Australia; Division of Clinical Geriatrics (L.-O.W.), NVS Department, Karolinska Institutet, Stockholm, Sweden; San Francisco Veterans Affairs Medical Center (M.W.W.); SeSMIT (Service for Medical Statistics and Information Technology) (P.P.), AFaR (Fatebenefratelli Association for Research), Fatebenefratelli Hospital, Isola Tiberina, Rome; and Unit of Clinical and Molecular Epidemiology (P.P.), IRCCS San Raffaele Pisana, Rome, Italy.
For ISTAART's NeuroImaging Professional Interest Area

Abstract

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

Recent acquisitions on the pathophysiology and natural history of Alzheimer disease (AD) have led researchers to propose alternatives to the traditional NINCDS-ADRDA diagnostic criteria. The International Working Group1,2 and National Institute on Aging–Alzheimer's Association (NIA-AA) criteria35 assign a key pathogenetic role to cerebral β-amyloidosis and neurodegeneration, hallmarked by senile plaques and neuronal tangles on microscopic examination. They further stipulate that positivity on one or more disease markers of brain amyloidosis (decreased levels of Aβ42 in the CSF and increased binding of amyloid imaging agents with PET) and neuronal injury (cortical temporoparietal hypometabolism on 18F-fluorodeoxyglucose [FDG]-PET, or hypoperfusion on SPECT, medial temporal atrophy on MRI, and increased tau or phospho-tau in the CSF) is associated with high likelihood that the patient's cognitive impairment is due to AD pathology.

The view is largely shared that the criteria, although potentially applicable, are not ready to be widely used in routine clinical practice,69 although a fluorinated ligand10 is qualified by US and European Union regulatory agencies,11,12 and amyloid PET and hippocampal volume are qualified by the latter for enrichment in clinical trials of AD modifiers.13,14 None of these biomarkers, neither imaging nor fluid, is reimbursed by health care providers or third party payers. However, some specialized clinical services with the appropriate knowledge and facilities are using biomarkers as adjuncts in the diagnostic process, supporting the practical urgency of quick progression on the track of criteria validation. In this context, the intrinsic test characteristics of biomarkers will represent a key factor for successful validation.

A number of reviews are available on the diagnostic accuracy of imaging biomarkers. Reviews have generally focused on single modality markers (i.e., MRI, FDG-PET, amyloid PET, or perfusion SPECT markers), and only a few have addressed accuracy across different modalities (e.g., MRI vs FDG-PET markers). Still fewer have studied diagnostic accuracy across different operating procedures, and none has addressed diagnostic accuracy of imaging biomarkers across different modalities and operating procedures. The latter effort is important to appreciate the relevance of modality and operating procedure on diagnostic accuracy. This information will help in designing clinical research studies aimed at validating the new diagnostic criteria for AD, and contribute to the progression of imaging biomarkers from informal diagnostic adjuncts to fully validated biomarkers.

We aimed at estimating the diagnostic and prognostic accuracy of different AD imaging biomarkers (here called “markers”) and their operating procedures (here called “metrics”), and to investigate the amount and source of variance among them. This review was conceived by the Neuroimaging Professional Interest Area, a group of clinical imaging scientists borne of the Alzheimer's Imaging Consortium and the specialist branch of the International Society to Advance Alzheimer's Research and Treatment (ISTAART) of the AA, in the context of its mission to promote the appropriate use of imaging in clinical and research contexts. The views expressed herein are those of the authors and do not represent a formal position or endorsement by the AA.

METHODS

Inclusion and exclusion criteria.

We performed a search on the PubMed database for literature published between 1989 and April 2012, using combined specific terms of AD, accuracy, and biomarkers: “condition AND marker AND submarker AND (accuracy OR sensitivity OR specificity),” where conditions were “Alzheimer's disease” and “mild cognitive impairment,” markers were “amyloid PET,” “SPECT or SPET,” “18F-FDG PET,” “magnetic resonance,” whereas submarkers were “18F” and “11C-PiB” for amyloid PET; “hippocampus,” “amygdala,” “entorhinal cortex,” and “temporal horn” for MRI; and “99mTc-HMPAO” and “99mTc-ECD or 123I-IMP” for SPECT. The “related articles” feature in PubMed for the selected research studies and references of retrieved articles were also screened to maximize the probability of finding additional relevant studies. We extracted single studies from reviews and meta-analyses1526 and addressed them individually. The search was limited to articles involving human subjects and written in English.

We included studies reporting sensitivity and specificity for each single analytic method for each biomarker (“metric”), and the number and the diagnosis of subjects for each comparison group. The clinical diagnosis was the comparator between different studies. For mild cognitive impairment (MCI), we included only studies that considered sensitivity as the correct classification of patients with MCI who subsequently progressed to AD dementia (pMCI) vs patients with MCI who did not progress (npMCI).

We excluded studies if they did not i) study patients with AD or MCI; ii) report numerical data for sensitivity and specificity; iii) explicitly state procedures for marker measurement; iv) assess the diagnostic performance of individual imaging biomarkers (e.g., accuracy of clinical diagnosis plus biomarkers, or a panel of biomarkers); v) disaggregate pMCI from npMCI; or vi) provide information on group size. Studies of AD vs other types of dementia were not considered because of i) the low number of available studies, and ii) the fact that we should have further disaggregated studies not only by markers by metrics but also by non-AD conditions, thus resulting in an unacceptably small group size per cell. We excluded studies comparing healthy elderly people and patients with MCI because of the huge etiologic heterogeneity of the MCI group, and studies of patients with MCI who progressed to non-AD dementias.

Metrics.

The selected studies were classified based on the specific marker acquisition and analytic approach (metric) (figure 1). Metrics are described below for each marker.

Figure 1
Markers, submarkers, and metrics reviewed in the current study

Amyloid imaging agents with PET.

Metrics include: i) visual read, the qualitative assessment of cortical ligand uptake for each image; ii) standardized uptake value ratio, the quantitative analysis of the ratio of cortical ligand uptake to a reference region for each image; and iii) distribution volume ratio, the quantitative analysis of the ratio of cortical ligand distribution volume to the cerebellar uptake for each image.

Temporoparietal hypometabolism on 18F-FDG-PET.

Metrics include: i) computer-aided visual read (Neurostat/3D-SSP, http://www.rad.washington.edu/research/Research/groups/nbl/neurostat-3d-ssp), which uses the 3-dimensional stereotactic surface projection technique through the Neurostat automated image analysis procedure, comparing each image on a pixel-by-pixel basis with a normative reference database, and producing parametric z score images; ii) t-sum/hypometabolic convergence index, the automated summary measures of AD-related hypometabolism based on the comparison of individual images with a normative reference dataset in a predefined AD mask (t-sum score is computed as voxel-by-voxel sum of t scores in a predefined AD-pattern mask,27 whereas the hypometabolic convergence index is calculated as the inner product of the individual Z-map and a predefined AD Z-map28); iii) computer-aided visual read using single-case statistical parametric mapping (sc-SPM) (http://www.fil.ion.ucl.ac.uk/spm), computing a score as the average metabolism on a set of meta-analytically derived regions of interest reflecting the AD hypometabolism pattern; and iv) visual read, the qualitative assessment of cortical metabolism for each image.

Temporoparietal hypoperfusion on SPECT or SPET.

Metrics include: i) visual read, the qualitative assessment of cortical perfusion for each individual image; and ii) quantitative/semiquantitative assessment, the quantification of cortical perfusion for each image.

Medial temporal atrophy on structural MRI.

Metrics include: i) visual read, the qualitative assessment of structure atrophy using Likert scales; ii) manual segmentation, the volumetric measurement through manual segmentation; iii) automated volumetry measurement computed through automated segmentation algorithms (FreeSurfer, which implements the subcortical segmentation by probabilistic segmentation based on a prior anatomical model29,30; AdaBoost-ACM, a “machine learning” method that learns features to guide segmentation31; BrainVISA SASHA, the deformation constraint approach based on prior knowledge of anatomical features automatically retrieved from MRI data32); and iv) linear measure, the manual measurement of the medial temporal lobe and the temporal horn of the lateral ventricle.

Table 1 suggests that metrics are remarkably heterogeneous for acquisition procedures, automation, stability, intensivity (in terms of human or machine time), availability of a normative population and threshold, and cost.

Table 1
Technical features of imaging metrics

Outcome measure.

To investigate the variability attributable to markers, submarkers, and metrics, we chose the likelihood ratio (LR). We preferred this to the more traditional sensitivity and specificity because it combines information of both sensitivity and specificity and is not affected by arbitrary thresholds that authors may choose to maximize the specificity or sensitivity of a test. Positive and negative LRs (LR+ and LR−) were computed as follows: LR+ = sensitivity/(100 − specificity) and LR− = (100 − sensitivity)/specificity. LR+ ≥5 and LR− ≤0.2 are generally regarded as clinically meaningful, i.e., diagnostically useful.33 We analyzed separately the accuracy for the discrimination of persons with AD from healthy elderly subjects (“diagnostic,” dementia stage) and for the discrimination of pMCI from npMCI (“prognostic,” MCI stage).

To obtain pooled measures of sensitivity and specificity, we used a classic Bayesian approach.34 (Details are provided in the supplementary material on the Neurology® Web site at www.neurology.org.) The estimation was repeated for each set of studies that investigated the same operating metrics on the same type of diagnostic groups.

Statistical analyses were performed with SPSS 12.0.1 (SPSS Inc., Chicago, IL) using 1-way analysis of variance (ANOVA) and nested ANOVA to test whether diagnostic and prognostic LR+ and LR− variability was attributable to differences among markers, metrics, and submarkers or attributable to variability among the metrics within markers, among the metrics within submarkers, or among the submarkers within markers. Statistical analyses and plots were restricted to metrics used by at least 3 studies. Through a linear regression analysis, we investigated the effect of age, disease severity, group size, and follow-up duration on sensitivity, specificity, and LR values.

RESULTS

Table 2 shows sensitivity and specificity values pooled across markers, submarkers, and metrics. Diagnostic accuracy was highest for amyloid imaging and progressively lower for 18F-FDG-PET, SPECT, and MRI. Prognostic accuracy had a similar pattern across markers, but was generally lower than diagnostic accuracy.

Table 2
Accuracy figures of imaging markers for AD at the dementia and MCI stagesa

LR analysis, dementia stage.

The analysis of LR+ (figure 2A) mirrored the accuracy analysis pattern; it was best for amyloid imaging (9.4) and poorest for MRI (4.4). Considering amyloid imaging submarkers, LR+ values were best for 18F ligands, whereas for MRI submarkers, the best were for temporal horn and the poorest for entorhinal cortex.

Figure 2
Diagnostic (A) positive and (B) negative likelihood ratio (LR+ and LR−) for correct classification between patients with Alzheimer disease and healthy subjects broken down by markers by metrics and by markers by submarkers

At the metrics level, the variability of LR+ was often as high as between markers, in particular for 18F-FDG-PET (range: 13.3–2.4), and for MRI (10.7–4.2). The variability among metrics was lower for the other 2 markers.

In LR− (figure 2B), for markers, the best values were for amyloid imaging (0.08) and the poorest for MRI (0.25). LR− values across amyloid imaging submarkers were rather homogeneous and little variation was also detected for MRI submarkers.

The variability of LR− of metrics was much higher, especially for amyloid imaging (0.01–0.10), and for 18F-FDG-PET (0.05–0.23). Variability among metrics was lower for the other 2 markers: 0.21 to 0.32 (MRI metrics), and 0.13 to 0.17 (SPECT metrics). For detailed information, see table e-1.

The variability of LR+ within metrics was even greater than across markers and metrics. Many metrics spanned 2 orders of magnitude, LR+ ranging from the poorest values between 1 and 3 up to between 70 and 100 (figure 2A). The variability of LR− within metrics was similar, spanning 2 orders of magnitude from 0.01 to 1.00 (figure 2B).

LR analysis, MCI stage.

Prognostic was generally poorer than diagnostic LR+ figures, being more than 5 for only 18F-FDG-PET (7.5). The pattern was also different; the second best LR+ value was that of MRI (2.6), followed by SPECT (2.2), and by amyloid imaging (1.7). It should be noted, however, that the number of studies contributing to prognostic LR+ estimation was much lower than that of diagnostic LR+. Considering MRI submarkers, prognostic LR+ was 2.9 for hippocampus and 2.2 for entorhinal cortex (figure 3A).

Figure 3
Prognostic (A) positive and (B) negative likelihood ratio (LR+ and LR−) for correct classification of patients with progressed vs nonprogressed mild cognitive impairment, broken down by markers by metrics and by markers by submarkers

In analogy with the pattern of diagnostic LR+, the variability across metrics was in some cases at least as large as that across markers. Prognostic LR+ of 18F-FDG-PET metrics ranged from 12.8 to 1.7. The variability across MRI metrics was lower (3.2–1.8).

For markers, LR− values (figure 3B) were best for amyloid imaging (0.11) and poorest for MRI (0.49) and 18F-FDG-PET (0.50). For MRI submarkers, LR− was 0.49 for hippocampus and 0.56 for entorhinal cortex.

Again, LR− values of 18F-FDG-PET metrics were quite heterogeneous (0.08–0.64), whereas the variability across MRI metrics was lower (0.46–0.50). For details, see table e-1.

The variability of prognostic LR+ within metrics spanned 1 order of magnitude, with few exceptions spanning 2 orders of magnitude (from approximately 1 to 10). The variability of LR− within metrics was similar, with a few exceptions spanning 2 orders of magnitude (18F-FDG-PET sc-SPM and amyloid PET–standardized uptake value ratio) (figure 3B).

Proportion of explained variance of LR estimates, dementia stage.

Markers accounted for 11% of LR+ and 24% of LR− variance and metrics for 13% and 29%, respectively (figure 4A). When markers were divided into “functional” (18F-FDG-PET and SPECT) and “structural” (MRI), they accounted for 12% of LR+ variance. Of all metrics, those with the largest variability were 18F-FDG-PET metrics (39%) for LR+, and MRI metrics (37%) for LR−. The variance of LR− explained by metrics remained significant even when tested with the more stringent nested ANOVA within markers (17%) and submarkers (15%). When restricted to MRI, nested ANOVA analysis showed that metrics within MRI submarkers accounted for 41% of diagnostic LR− variance.

Figure 4
Proportion of explained variance and significance of positive and negative likelihood ratio (LR+ and LR−) for correct classification between (A) patients with Alzheimer disease and healthy subjects, and (B) patients with progressed and nonprogressed ...

Proportion of explained variance of LR estimates, MCI stage.

When compared with diagnostic LR+ variance, both markers and metrics accounted for a larger proportion of prognostic variance (18% and 62%, respectively) (figure 4B). In contrast, compared with diagnostic LR− variance, markers and metrics accounted for a lower proportion of prognostic variance, 16% and 18%, respectively.

Similarly to diagnostic metrics, the prognostic metrics with the largest LR+ variability were 18F-FDG-PET metrics (82%). Metrics accounted for 25% of prognostic LR+ variance of the MRI marker. When considered together, SPECT and 18F-FDG-PET metrics accounted for 78% of prognostic LR+ variance.

The prognostic variance of metrics remained significant even when tested with nested ANOVA within markers (68%). When restricted to SPECT and 18F-FDG-PET metrics, nested ANOVA analysis showed that these functional metrics accounted for 86% of prognostic variance.

Effect of confounders on LR estimates.

Specific analyses regarding the effect of study group size, follow-up duration, age, and disease severity on accuracy figures are reported in the supplementary material.

DISCUSSION

We have estimated diagnostic and prognostic accuracy of different AD markers as well as pertinent metrics, and the amount and source of variance among them. We have shown that the diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the type of biomarker itself. While acknowledging that imaging biomarkers capture different neurobiological constructs (brain amyloidosis, neuronal injury at the molecular level, and neuronal injury at the gross structural level), this observation provides empirical support to current efforts aimed at developing standard operating procedures (SOPs) for AD biomarkers.7,35 Such efforts are key to the use of imaging biomarkers in the diagnostic routine and in clinical trials.

Diagnostic LRs were generally better than prognostic LRs: diagnostic LRs+ were approximately >5 for all markers and metrics (except 18F-FDG-PET visual read), and diagnostic LRs− were generally <0.20, except for MRI metrics. This is expected in that biological changes in patients with pMCI are milder than in patients with AD dementia.3641 The increasing awareness of AD and options for early diagnosis make biomarkers particularly useful in clinical practice to distinguish pMCI from npMCI. Here, LRs+ were <3 for all metrics and markers, except 18F-FDG-PET; the pattern was similar for LR−, where all markers and the majority of metrics yielded LR− >0.45, except amyloid imaging. Alternatively, better LRs of diagnostic studies might be attributable to cross-sectional case-control studies yielding optimistic estimates of sensitivity and specificity.42

LR point estimates of amyloid imaging metrics tended to be better than the other metrics. This is in line with the current understanding of the AD pathophysiology, positing that brain amyloidosis is a necessary condition for AD-related neurodegeneration to take place.4,43 On the contrary, LR+ and LR− figures were the poorest for MRI metrics in almost all conditions. This is expected in view of the little specificity of medial temporal atrophy, which is featured in AD as well as in a proportion of cognitively healthy older persons.44 It should be emphasized, however, that because of limitations of the current review, we cannot conclude that a metric or a marker is better than another for clinical use. For instance, the number of studies with amyloid imaging is by far lower than those with MRI and, in the prognostic condition, also than those with 18F-FDG-PET. More amyloid imaging studies, possibly focused on differential diagnosis, are needed to consolidate the pertinent estimates on LRs and to allow comparisons among different tracers.

The metrics with the largest variability were those of 18F-FDG-PET. Interestingly, diagnostic LR+ for t-sum was better than sc-SPM, and vice versa for prognostic LR+. This attests to the benefits of standardizing 18F-FDG-PET metrics.

Importantly, if the variability of diagnostic LRs across metrics varied by 1 order of magnitude (i.e., 10-fold), the variability within a metric varied by as many as 2 orders of magnitude (i.e., 100-fold). The within-metric variability of prognostic LRs also varied by 1 order of magnitude. This observation militates in favor of standardization of metrics, which should reduce this 100-fold variability to close to zero.

Metrics vary for a number of features such as dependency on i) a specific (sometimes nonroutine) image acquisition protocol and ii) a human rater and automation; iii) stability over time (test-retest reliability) and across raters (interrater reliability); iv) feasibility in routine clinical settings, where human and technological resources are tailored to the use of routine tests; availability of v) rigorously standardized operating procedures for measurement vi) of a reference normative population and vii) of reliable abnormality thresholds; and viii) cost of the overall acquisition and measurement procedure. All of the above issues should be addressed by standardization efforts for metrics to be adopted in the clinical routine and to be used as the reference for validation of automated algorithms. The practical message to clinical neurologists is that using AD markers in the diagnostic pathway of patients with cognitive impairment is not a guarantee of greater accuracy per se. Because accuracy largely depends on how a marker is analyzed, clinicians wishing to follow the International Working Group or NIA-AA diagnostic criteria can i) use metrics for which SOPs are available and whose accuracy is known (e.g., FreeSurfer/NeuroQuant for medial temporal atrophy or 18F-florbetapir for cortical amyloid burden), ii) empirically measure in their own setting the accuracy of the metric they wish to use, or iii) wait for SOPs to be developed for other metrics.

This review has a number of limitations that should be noted. Because of the small number of studies, we did not address the accuracy of imaging biomarkers for the differential diagnosis of dementia type (AD vs Lewy body dementia, vs frontotemporal degeneration, etc.). With the hopeful advent of drugs affecting specific core pathophysiologic substrates of AD, this issue may become of greater relevance and need to be properly addressed, also because differential diagnosis is crucial in the clinical practice. However, we found that how a marker is measured is as relevant as which marker is considered even for a less “clinically relevant” and “easier” comparison (AD vs healthy), further reinforcing the need of standardized measurement of biomarkers.

We accepted the definitions of AD and MCI adopted by the reviewed studies, including exclusion criteria (e.g., vascular disease, medications), thus accepting the inherent clinical heterogeneity, which may be enhanced by the fact that some patients were from research cohorts. We did not consider neuropathologic diagnosis of AD because few studies have histopathologic confirmation of AD diagnosis and we recognized that this is a limitation of our review.

Data regarding the “classification” of AD dementia vs cognitively normal elders is only a necessary but not sufficient indicator of a test's value and does not reflect its diagnostic accuracy in clinical settings. Further tests of “diagnostic” value would be those that help in the differential diagnosis (e.g., among different dementia cases) for predicting postmortem neuropathology and a person's clinical course (as in the MCI analysis), and eventually, for predicting response to treatment. Another limitation pertains to the use of imaging markers for prognosis4 and differential diagnosis5 in the context of the new criteria. Here, imaging needs to be used together with biological (CSF) markers, and the contribution of biological markers to LRs of imaging markers will need to be investigated in future studies with pathologic confirmation.

The definition we chose to classify metrics should be taken with due caution: neurodegenerative changes in the medial temporal lobe have largely been assessed using volumetric MRI, but evidence showed that they can also be accurately studied with FDG-PET.45 Confounders had little effect on diagnostic and prognostic accuracy values, with the exception of the positive association of age with LR− and its negative association with specificity in AD, and negative association of age with LR+ and specificity in MCI stage. We believe that this observation is attributable to the relatively higher frequency of abnormal markers in elderly persons despite no disease.46 For the MCI stage, there was a significant effect of study group size on LR−, indicating a slight increase of false-negative rates for a given true-positive rate with increasing size. This is understandable in light of observations that smaller studies frequently show better accuracy values because of stricter selection of cases. Lastly, it should be noted that some sources of variability (e.g., ethnicity, application of diagnostic criteria, inclusion and exclusion criteria, case mix, socioeconomic status) might have escaped our analyses because of the intrinsic limitations of this type of meta-analysis.

Supplementary Material

Data Supplement:
Data Supplement:

ACKNOWLEDGMENT

The authors thank Marco Lorenzi, PhD, for his valuable help with data analysis.

GLOSSARY

AA
Alzheimer's Association
AD
Alzheimer disease
ANOVA
analysis of variance
FDG
fluorodeoxyglucose
ISTAART
International Society to Advance Alzheimer's Research and Treatments
LR
likelihood ratio
MCI
mild cognitive impairment
NIA
National Institute on Aging
NINCDS-ADRDA
National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association
npMCI
nonprogressed mild cognitive impairment
pMCI
progressed mild cognitive impairment
sc-SPM
single-case statistical parametric mapping
SOP
standard operating procedure

Footnotes

Supplemental data at www.neurology.org

AUTHOR CONTRIBUTIONS

Drafting/revising the manuscript for content: Frisoni, Bocchetta, Pasqualetti, Chételat, Rabinovici, Herholz, Kaye, Jack, Rowe, Jagust, Wahlund, Brooks, Nordberg, Scheltens, Reiman, Weiner, de Leon. Study concept or design: Frisoni, DeCarli, Barkhof, Herholz, Kaye, Jack, Rowe, Jagust, Wahlund, Brooks, Nordberg, Scheltens, Reiman, Fox, Black, Sperling, Johnson, Weiner, Carrillo, Thies. Analysis or interpretation of data: Frisoni, Bocchetta, Pasqualetti. Statistical analysis: Bocchetta, Pasqualetti. Study supervision or coordination: Frisoni.

STUDY FUNDING

This study was partially funded by the Alzheimer's Association grant IIRG-10-174022, “A Harmonized Protocol for Hippocampal Volumetry: An EADC-ADNI Effort.”

DISCLOSURE

G. Frisoni has served on advisory boards for Lilly, BMS, Bayer, Lundbeck, Elan, AstraZeneca, Pfizer, TauRx, Wyeth, and GE; he is a member of the editorial boards of Lancet Neurology, Aging Clinical and Experimental Research, Alzheimer Disease & Associated Disorders, Neurodegenerative Diseases, and Imaging Section Editor of Neurobiology of Aging; he has received grants from Wyeth International, Lilly International, Lundbeck Italia, GE International, Avid/Lilly, and the Alzheimer's Association. M. Bocchetta, G. Chételat, and G. Rabinovici report no disclosures. M. de Leon has served on the scientific advisory board for Roche; he is a holder of image analysis patents through New York University. J. Kaye received research support from the Department of Veterans Affairs and the NIH; individuals that work in the research centers he directs received research support from Johnson & Johnson, Roche, and Bristol-Myers Squibb. J. Kaye was compensated for serving on a data monitoring committee for Eli Lilly, and as a paid advisor for Janssen Pharmaceutical; he received reimbursement through Medicare or commercial insurance plans for providing clinical assessment and care for patients; he has been salaried to see patients at the Portland VA Medical Center; he served as an unpaid Vice-Chair for the International Professional Interest Area Work Group of the ISTAART and as an unpaid Commissioner for the Center for Aging Services and Technologies; he serves on the editorial advisory board of the journals Alzheimer's & Dementia and Frontiers of Aging Neuroscience. E. Reiman served as a scientific advisor to Sygnis, AstraZeneca, Bayer, Eisai, Elan, Eli Lilly, GlaxoSmithKline, Intellect, Link Medicine, Novartis, Siemens, and Takeda; he has had research contracts with AstraZeneca and Avid/Eli Lilly; a patent pending for a biomarker strategy to evaluate preclinical AD treatments (through Banner Health); and research grants from the National Institute on Aging, Anonymous Foundation, Nomis Foundation, Banner Alzheimer's Foundation, and the State of Arizona. P. Scheltens serves on the advisory boards of Genentech, Novartis, Pfizer, Roche, Danone, Nutricia, Jansen AI, Baxter, and Lundbeck; he has been a speaker at symposia organized by Lundbeck, Lilly, Merz, Pfizer, Jansen AI, Danone, Novartis, Roche, and Genentech; he serves on the editorial board of Alzheimer's Research & Therapy and Alzheimer Disease & Associated Disorders; he is a member of the scientific advisory board of the European Union Joint Programming Initiative and the French National Plan Alzheimer. The Alzheimer Center receives unrestricted funding from various sources through the VUmc Fonds; he receives no personal compensation for the activities mentioned above. F. Barkhof reports no disclosures. S. Black has received funding in the past 2 years for ad hoc consulting from Pfizer, Novartis, Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Elan. She has received speaker's honoraria for CME from Pfizer, Novartis, and Eisai. Dr. Black's unit has received contract research funds from GlaxoSmithKline, Roche, Pfizer, and Elan and research funds from the Canadian Institutes of Health Research (MOP-13129, MOP-106485, MOP-82744), NIH (ADNI), Heart and Stroke Foundation Centre for Stroke Recovery, Heart and Stroke Foundation of Canada (T6075, T6383), Alzheimer's Drug Discovery Foundation, W. Garfield Weston Foundation, and Brain Canada. She has received salary support from the Brill Chair in Neurology, the Sunnybrook Research Institute, and the Department of Medicine, University of Toronto. D. Brooks and M. Carrillo report no disclosures. N. Fox holds a patent for QA Box that may accrue revenue. In the last 2 years, his research group has received payment for consultancy or for conducting studies from AVID, Bristol-Myers Squibb, Elan Pharmaceuticals, Eisai, Lilly Research Laboratories, GE Healthcare, IXICO, Janssen Alzheimer Immunotherapy, Johnson & Johnson, Janssen-Cilag, Lundbeck, Neurochem Inc., Pfizer Inc., Sanofi-Aventis, and Wyeth Pharmaceuticals. He receives research support from MRC (G0801306 [PI], G0601846 [PI]), NIH (U01 AG024904 (coinvestigator; subcontract), Alzheimer Research Trust (ART/RF/2007/1 [PI]), and NIHR (senior investigator). K. Herholz reports no disclosures. A. Nordberg has been the PI for clinical trials sponsored by TorreyPines Therapeutics, GSK, Wyeth, and Bayer Pharma; she served on the advisory board for Elan, Pfizer, GSK, Novartis, Lundbeck AB, Johnson & Johnson, GE Healthcare, and Avid; she received honorarium for lectures from Novartis, Janssen-Cilag, Pfizer, and Merck, and research grants from Novartis, Pfizer, GE Healthcare, Johnson & Johnson, and Bayer Pharma; she owns no stocks and is a member of the editorial advisory board for Current Alzheimer Research, Journal of Alzheimer's Disease, and Alzheimer's Research & Therapy. 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. W. Jagust has served as a consultant to Siemens, Genentech, TauRx, and Janssen Alzheimer Immunotherapy; he receives research support from NIH (AG034570, AG025303). K. Johnson and C. Rowe report no disclosures. R. Sperling has served as a paid consultant for Bayer, Biogen Idec, Bristol-Myers Squibb, Eisai, Janssen Alzheimer Immunotherapy, Pfizer, Merck, Roche, Satori, 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. W. Thies and L. Wahlund report no disclosures. M. Weiner served on the scientific advisory board for Lilly, Araclon and Institut Catala de Neurociencies Aplicades, Gulf War Veterans Illnesses Advisory Committee, VACO, Biogen Idec, Pfizer, and BOLT International; he is a consultant for AstraZeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics Ltd., Bayer Healthcare, Biogen Idec, ExonHit Therapeutics, SA, Servier, Synarc, Pfizer, Janssen, Harvard University, and KLJ Associates; he received funds for travel from NeuroVigil, Inc., CHRU-Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, University of California, San Diego–ADNI, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, CTAD (Clinical Trials on Alzheimer's Disease), Pfizer, AD PD meeting, Paul Sabatier University, Novartis, Tohoku University, Fundacio ACE, and Travel eDreams, Inc.; he is a member of the editorial advisory board of Alzheimer's & Dementia and MRI; he received honoraria from NeuroVigil, Inc., Insitut Catala de Neurociencies Aplicades, PMDA/Japanese Ministry of Health, Labour, and Welfare, Tohoku University, and Alzheimer's Drug Discovery Foundation; he received research support from commercial (Merck and Avid) and government (DOD and VA) entities; he holds stock options from Synarc and Elan; he received funds from organizations contributing to the Foundation for NIH and thus to the NIA-funded Alzheimer's Disease Neuroimaging Initiative: Abbott, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Anonymous Foundation, AstraZeneca, Bayer Healthcare, BioClinica, Inc. (ADNI 2), Bristol-Myers Squibb, Cure Alzheimer's Fund, Eisai, Elan, Gene Network Sciences, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck, Novartis, Pfizer Inc., Roche, Schering-Plough, Synarc, and Wyeth. P. Pasqualetti and C. DeCarli report no disclosures. Go to Neurology.org for full disclosures.

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