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Logo of neurologyNeurologyAmerican Academy of Neurology
 
Neurology. 2013 October 8; 81(15): 1332–1341.
PMCID: PMC3806926

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Marka van Blitterswijk, 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

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
Matthew C. Baker, BSc,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. US Patent #12/302,691 [Detecting and Treating Dementia (2008)] and US Patent #12/413,869 [Methods and Materials for Detecting and Treating Dementia (2009)].

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
Mariely DeJesus-Hernandez, BS,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. Methods and materials related for detecting the presence of an expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 that causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis.

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
Roberta Ghidoni, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1)Frontiers in Bioscience, Managing Editor, 2010- lifetime, (2) JOURNAL OF ALZHEIMER'S DISEASE, associate editor, 2010-2015, (3)International Journal of Clinical and Experimental Medicine, associate editor, 2010-2013, (4) Dataset Papers in Medicine, editorial board, 2012-2013 (5) ISRN Geriatrics, editorial board, 2012-2013 (6) American Journal of Alzheimers Disease, associate editor, 2011-2013; (7)American Journal of Neurodegenerative, senior 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. (1)Italian Ministry of Health, Ricerca Corrente, PI, 2013

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Luisa Benussi, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

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

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Italian Ministry of Health, Ricerca Corrente, PI, 2013

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Elizabeth Finger, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Canadian Institute of Health Research, PI, 4 years

Research Support, Academic Entities:

  1. 1) Hasel Soper Foundation start up funds through the University of Western Ontario 2) Lawson Health Research Fund Internal Grant 3) University of Western Ontario Academic Development Fund Grant 4) Schulich School of Medicine and Dentistry

Research Support, Foundations and Societies:

  1. 1) Alzheimer Society of Canada 2) Alzheimer's Society of London and Middlesex

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
Ging-Yuek R. Hsiung, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Dr. Hsiung has received Speaker honoraria from Merck and Novartis.

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. Dr. Hsiung has received research support as a clinical trials site investigator from Baxter, Bristol-Myers-Squibb, Genentech, Hoffman-La Roche, and Pfizer, and has received honorarium for participation in expert review committee with Merck and Novartis.

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. Dr. Hsiung is supported by a Clinical Genetics Investigatorship award from the CIHR, and has received research funding from the CIHR, Alzheimer Society of Canada, and NIH.

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

Stock/Stock Options, Medical Equipment & Materials:

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Legal Proceedings:

  1. NONE
Brendan J. Kelley, MD,

Scientific Advisory Boards:

  1. Dr. Kelley has received compensation for serving on an advisory board for Lilly.

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Dr. Kelley has received honoraria from Lilly for speaking as part of the florbetapir reader training course.

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. Dr. Kelley serves as the site PI for a trial sponsored by Novartis.

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
Melissa E. Murray, 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
Nicola J. Rutherford, BSc,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

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Publishing Royalties:

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Employment, Commercial Entity:

  1. NONE

Consultancies:

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  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
Patricia E. Brown, MS,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

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Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

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  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 Ravenscroft,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

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Patents:

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Publishing Royalties:

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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
Bianca Mullen, 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
Peter E.A. Ash, 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
Kevin F. Bieniek, BS,

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
Kimmo J. Hatanpaa, 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

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. 1 R01NS062080-01A2 (Amyn Habib) 9/29/2009- 8/30/2013 0.6 calendar NINDS Role: Co-investigator A role for RIP1 in gliomagenesis The major goal of this project is to investigate the role of RIP1 in gliomagenesis. 1 R01 NS065195-01A1 (Robert Bachoo) 7/1/2010-6/30/2015 1.2 calendar NINDS Role: Co-investigator Genetic Dissection of Glioblastoma: Cell of Origin The major goal of this project is to investigate the genomic and proteomic profile of glioblastoma 5 P30 AG012300-16 (Roger Rosenberg) 5/17/2005-3/31/2015 0.4 calendar NIH/NIA Role: Co-investigator Neurobiology of Alzheimer's Disease and Aging-Core D Neuropathology The major goal of this project is to provide neuropathology confirmation of the clinical diagnoses of patients followed in the Alzheimer's Disease Center and to support the neuropathology-related research projects of the Center

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
Anna Karydas, BA,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Elisabeth McCarty Wood, 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
Giovanni Coppola, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. I receive research support from (1) NIH, RC1AG0356101, PI, 2009-2011, (2) NIH, R01 AG26938, key personnel, 2005-2011, (3) NIH, P01 AG19724, key personnel, 2007-2012, (4) NIH, P50 AG023501, key personnel, 2009-2011, (5) NIH, 1RC2MH089921, key personnel, 2009-2011, (6) 1R01HD065298, Key personnel, 2009-2011, (7) CHDI, (8) Takeda Pharmaceutical Company

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) the Consortium for Frontotemporal Dementia Research (2) Adelson Medical Research Foundation (2010) (3) the Tau Consortium (4) The Easton Consortium (5) CHDI (6) Takeda Pharmaceutical Company

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
Eileen H. Bigio, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Mayo Clinic, honorarium American Association of Neuropathologists, honorarium

Editorial Boards:

  1. (1) Journal of Neuropathology and Experimental Neurology, editorial board, 2007-current (2) Acta Neuropathologica, editorial board, 2009-current (3) Brain Pathology, editorial board, 2009-current

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, P30 AG13854, Role: PI of Neuropathology Core, 7/1/12-6/30/13

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
Carol Lippa, MD,

Scientific Advisory Boards:

  1. non-profit entities: LBDA, AFTD, Alz Assn (Delaware Valley)

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. 1) Am J of Alzheimer's disease and other dementias, Editor, about 2008 -

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. DUCOM Neurology: Professor and Interim Chair, Neurology

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Elan; Danone, Pfizer, Janssen, Novartis

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
Michael J. Strong, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Amyotrophic Lateral Sclerosis, editorial advisory board, 2004 - current

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. Canadian Institutes of Health Research (CIHR) 2010 - 2013, PI, miRNA in ALS

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 G. Beach, MD, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Non profit university (Shiga Medical University and Tottori Medical University, Japan) paid for my travel and accomodations as well as an honororium February 9th through 15, 2012. Non profit organization: American Academy of Neurology paid for my travel to San Diego at the 2013 annual meeting and also paid me an honorarium.

Editorial Boards:

  1. Editorial advisory board member, Acta Neuropathologica, 2010 through present. No payment.

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. I have been employed since 1997 solely with the non- profit organizations Sun Health Research Institute and Banner Health.

Consultancies:

  1. Commercial entity, GE Healthcare, consultancy 2013.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Avid Radiopharmaceuticals; Bayer Healthcare; GE Healthcare

Research Support, Government Entities:

  1. July 1, 2006 – June 30, 2011, National Institute on Aging, Neuropathology Core; July 1, 2006 – December 21, 2008, Arizona Alzheimer's Consortium, Neuropathology Core; July 1, 2006 – June 30, 2007, National Alzheimer's Coordinating Center, Co-investigator; September 25, 2006 – August 31, 2010, National Institutes of Health, Co-investigator; October 1, 2008 - September 30, 2009, Arizona Biomedical Research Commission, Neuropathology Core; April 1, 2008 – March 31, 2012, National Institutes of Health, Co-investigator

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. 2013, Michael J. Fox Foundation for Parkinson's Research

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 S. Knopman, MD,

Scientific Advisory Boards:

  1. Lilly Pharmaceuticals, Data Safety Monitoring Board, ended 8/22/12; TauRx consultant 2012; Consultant, McGill University Alzheimer Program 9/19/12; Consultant Bluefield project (frontotemporal demantia) 2013

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1) Lecture, University of Toronto, March 2012 (2) Lecture, University of Pennsylvania, January 2013 (3) Lecture, St Johns Hospital, Jackson Hole Wyoming June 2013 (4) Lecture, Amer Soc Neuroradiol, San Diego CA, May 2013

Editorial Boards:

  1. Neurology, Deputy Editor

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. (1) Janssen Alzheimer Immunotherapy program 3/29/11: honorarium paid to my institution; (2) Merck Alzheimer program 11/5/11 paid to my institution. (3) TauRx: two presentations in clinical trial investigator meetings.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Janssen for Alzheimer clinical trial, (2) Forest Laboratories for clinical trial in FTLD with memantine, (3) Baxter Laboratories for Alzheimer Clinical trial

Research Support, Government Entities:

  1. NIH: R01-AG11378 ongoing, P50-AG 16574 (Mayo Alzheimer's Disease Research Center) ongoing, U01 AG 06786 (Mayo Alzheimer Disease Patient Registry) ongoing. NIH R01 AG32306 FTD Neuro-imaging;Initiative. 1U01HL096917-01 ARIC Dementia Study.AG 037551 Chronic Kidney Disease and Cognitive functioning.

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
Edward D. Huey, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NIH/NINDS grant #5R00NS060766-03, PI 1 year

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
Marsel Mesulam, MD,

Scientific Advisory Boards:

  1. Cure Alzheimer Fund, $1500 Association on Frontotemporal Dementia, $0

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Brain, Annals of Neurology, Human Brain Mapping, Journal of Cognitive Neuroscience- Member of Editorial Board, no compensation

Patents:

  1. NONE

Publishing Royalties:

  1. Principles of Behavioral and Cognitive Neurology, Oxford University Press

Employment, Commercial Entity:

  1. Yale Stanford University of Leuven Harvard International Neuropsychological Society, AAN Lecturer

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- AG13854 1996-now PI NIH- DC008552 2005-now 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
Thomas Bird, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Brain, Editorial Board, 2007-2013 Neurology Today, Editorial Board, 2005-2013

Patents:

  1. Mutations In PKCγ Are The Cause For Spinocerebellar Ataxia. US Patent Application under review. US Patent #7,655,401 B2 Granted 2-2-2010. Raskind WH, Bird TD, Chen DH, Brkanac Z. SIMPLE (LITAF/PIG7) Mutations Associated With A Human Demyelinating Neuropathy (Charcot-Marie-Tooth Disease Type 1C). US Patent Application under review (UW OTL-2955-3813-4249PT). Chance PF, Bird TD, Street VA, Goldy JD.

Publishing Royalties:

  1. Bird, TD: Genetic Factors in Alzheimer Disease and Dementia. In Speicher GM, Antonaraskis SE, Motulsky AG (eds), Human Genetics – Principles and Approaches, Springer-Verlag GmbH Biomedical Sciences, 4th Edition; 23.3:681-698, 2010.

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. Athena Diagnostics, Inc; 2000-2010

Other activities:

  1. Licensing fees from Athena Diagnostics Inc.

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Department of Veterans' Affairs, Merit Research Grant, PI, 2009-2013

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License fee payments, Technology or Inventions:

  1. Athena Diagnostics, Inc for

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
Charles L. White, III, MD,

Scientific Advisory Boards:

  1. Served as a scientific advisor for the Michael J. Fox Foundation for Parkinson's Research (2006-present)

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. Received travel funding and speaker honorarium from Elan Pharmaceuticals (2012). Received speaker honorarium from Leica Microsystems (2013).

Editorial Boards:

  1. Serve as associate editor for Journal of Neuropathology and Experimental Neurology (2013-present)

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Consultant for Elan Pharmaceuticals, Leica Microsystems, and Banner Health.

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. Funded as the Principal Investiagator on the Neuropathology Core of NIH grant AG12300 (1994-present)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Andrew Kertesz, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Cognitive and Behavioral neurology, Editorial board since 2003 Aphasiology since 1990

Patents:

  1. NONE

Publishing Royalties:

  1. The Western Aphasia battery, Pearson (Grune and Stratton) 1982

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. American Neurological Society: The John Whitaker professorship,

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
Dan H. Geschwind, MD, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1) Neuron 2007- (2) Neurogenetics 2006- (3) Neurobiology of Disease 2004- (4) Current Genomics 1999- (5) Biological Psychiatry 2006- (6) Autism Research 2007- (7) Encyclopedia of autism and related disorders 2009- (8) Biomed Central 2010-2013

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. (1) Great Point Partners, commercial entity (not public) (2) SynapDx, commercial entity (not public) (3) Versant Ventures, commercial entity (4) Roche Group, commercial entity

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Takeda Pharmaceutical Company

Research Support, Government Entities:

  1. (1) NIH/NIMH 9R01 MH100027-06 (Geschwind, PI), 03/25/13- 02/28/18 (2) NIH/NICHD 5P50 HD055784-06 (Geschwind co-Investigator) 09/04/12-05/31/17 (3) NIH/NIMH 5R37 MH060233-11 (Geschwind, PI) 07/10/99- 06/30/15 (4) NIH/NIMH 1R01 MH094714-02 (Geschwind, PI) 09/01/11- 08/31/15 (5) CIRM TR2-01814 (Geschwind co-Investigator, subaward from UCSD) 04/01/11-03/31/14 (6) NIH/NIMH 1R01 MH100028-01 (Geschwind PI of subaward from Yale) 08/01/12-07/31/17 (7) NIH/NINDS 1R01 NS073871-01A1 (Geschwind co-Investigator) 12/01/11-11/30/16 (8) NIH/NIA 5P01 AG019724-08 (Geschwind PI of subaward from UCSF) 09/01/12-8/31/17

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) The Simons Foundation (2) Adelson Medical Research Foundation (3) Fidelity Foundation

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Vivianna M. Van Deerlin, MD, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Member, Editorial Board,

Patents:

  1. NONE

Publishing Royalties:

  1. Molecular Pathology in Clinical Practice. Leonard DGB, Bagg A, Caliendo AM, Kaul KL, Van Deerlin VM (eds.). Springer, 2007 Notes: VM Van Deerlin, Section Editor, Identity Testing Section (pages 491-537). Royalties received

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 NS053488 NIH AG010124 NIH AG017586

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
Ronald C. Petersen, MD,

Scientific Advisory Boards:

  1. (1) Pfizer, Inc., Chair, Data Monitoring Committee ; (2) Janssen Alzheimer Immunotherapy, Chair, Data Monitoring Committee

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. Mild Cognitive Impairment,Oxford University Press, 2003

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. (1) Elan Pharmaceuticals, (2) GE Healthcare

Speakers' Bureaus:

  1. NONE

Other activities:

  1. Novartis CME lecture

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. National Institute on Aging: U01-AG006786 (PI) (1986-present) P50-AG016574 (PI) (1990-present) R01-AG011378 (Co-I) U01-AG024904 (Co-I) Non-financial disclosures: National Advisory Council on Aging, National Institute on Aging

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
Giuliano Binetti, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. 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
Bruce L. Miller, MD, PhD,

Scientific Advisory Boards:

  1. 1. Alzheimer's Disease Clinical Study (DSMB) 2. Tau Rx, Ltd. SAB 3. Bristol-Myers Squibb SAB 4. Siemens Moleceular Imaging 5. Eli Lilly US AD

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. 1. Neurocase, Editor, 2003- 2. ADAD, Associate Editor, 2009

Patents:

  1. NONE

Publishing Royalties:

  1. Behavioral Neurology of Dementia, Cambridge 2009 Handbook of Neurology, Elsevier 2009 The Human Frontal Lobes, Guilford, 2008

Employment, Commercial Entity:

  1. University of California, San Francisco A.W. and Mary Margaret Clausen Distinguished Professor in Neurology Director, Memory and Aging Center Adjunct Professor in Psychiatry UCSF School of Medicine

Consultancies:

  1. 1. Allon Pharmaceutircals - Steering Committee AL-108-231 2. Bristol-Myers Squibb - PSP SAB 3. TauRx - SAB bvFTD Trial 4. Siemens Molecular Imaging, Neurology SAB 5. Ely Lilly, US AD Advisory Board

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Novartis Research Grant

Research Support, Government Entities:

  1. 1. NIA P50 AG23501 PI, (2004-) 2. NIA P01 AG19724 PI, (2002-) 3. State of California Alzheimer's Center PI (1999-2013)

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Leonard Petrucelli, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. J. Neuroscience (Associate Editor) 2009-present Molecular Neurodegeneration (Associate Editor) 2010- present PLoS One (Academic Editor) 2010-present

Patents:

  1. “C9orf72 Rantibody as a Diagnostic Test for C9orf72 Mutation Carriers. Development of an assay to detect c9orf72 RAN translation products in CSF/blood.

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. Lundbeck Scientific research Agreement Acetylon Scientific research Agreement SK Scientific research Agreement

Research Support, Government Entities:

  1. National Institutes of Health/National Institute on Aging [R01AG026251 (LP)], National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964-01 (LP), R01 NS077402 (LP), the Department of Defense [W81XWH-10-1-0512-1 (LP) and W81XWH- 09-1-0315AL093108 (LP)], andNIH ES20395-01

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. Lundbeck - Scientific Research Agreement

Royalty Payments, Technology or Inventions:

  1. 1. Licensing of TDP-43 antibody

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Zbigniew K. Wszolek, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Parkinsonism and Related Disorder, Co-Editor-in Chief, 2008-present; European Journal of Neurology, Regional Editor, 2007-present; Advances in Rehabilitation, Editorial Board member, 2005-present; Medical Journal of the Rzeszow University and the National Medicines Institute, Editorial Board member, 2005-present; Clinical and Experimental Medical Letters, Editorial Board member, 2006-present.

Patents:

  1. Identification of Mutations in PARK8, a Locus for Familial Parkinson's Disease, Mayo Clinic case #2004-185; Identification of a Novel LRRK2 Mutation, 6055G>A (G2019S), Linked to Autosomal Dominant Parkinsonism in Families from Several European Populations, Mayo Clinic case #2004-291

Publishing Royalties:

  1. Parkinsonism and Related Disorders, Elsevier, 2011, 2012, 2013; European Journal of Neurology, Wiley- Blackwell, 2011, 2012, 2013.

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/NINDS P50 NS072187

Research Support, Academic Entities:

  1. Mayo Clinic Center for Regenerative Medicine

Research Support, Foundations and Societies:

  1. Dystonia Medical Research Foundation and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. Mayo Clinic and I have a financial interest in technologies entitled, “Identification of Mutations in PARK8, a Locus for Familial Parkinson's Disease” and “Identification of a Novel LRRK2 Mutation, 6055G>A (G2019S), Linked to Autosomal Dominant Parkinsonism in Families from Several European Populations”. Those technologies have been licensed to a commercial entity, and to date, I have received royalties through Mayo Clinic in accordance with its royalty sharing policies.

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Kevin B. Boylan, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Biogen Idec (2) Cytokinetics, Inc. (3) Neuraltus Pharmaceuticals

Research Support, Government Entities:

  1. (1) NINDS, 1 R21 NS074121- 01, Co-I

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) ALS Association (2) ALS Therapy Alliance

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
Neill R. Graff-Radford, MBBCh,

Scientific Advisory Boards:

  1. (1) Codman, Scientific Advisory Board; (2) Baxter, DSMB

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1) The Neurolologist, Editorial Board; (2) Alzheimer Disease and Therapy, Editorial Board

Patents:

  1. NONE

Publishing Royalties:

  1. I received royalties for an article in UpToDate

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) TauRx FTD multicenter study (2) Allon grant for PSP multicenter study

Research Support, Government Entities:

  1. (1) NIA P50AG16574 coinvestigator ADRC; (2) NIA U24AG26395 Site PI LOAD study; (3) NIA U01AG24904 Site PI ADNI; (4) NIA R01AG06656 Coinvestigator

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  1. NONE

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Ian R. Mackenzie, MD,

Scientific Advisory Boards:

  1. AFTD

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. ALS Society of Canada (travel) AAIC(travel) CTAD (travel) FBRI (travel) ICFTD (travel) NGFN (travel)

Editorial Boards:

  1. J Neuroinflamm, 2011-13 Clin Neuropathol, 2011-13 J Neuropathol Exp Neurol, 2011-13 J Neuropathol Appl Neurobiol, 2011-13 Acta Neuropathol, 2012-13 Am J Neurodeg Dis 2012-13

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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

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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

Research Support, Foundations and Societies:

  1. Pacific Alzheimer Research Foundation Michael Smith Foundation for Health Research Canadian Institutes for Health Research

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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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Bradley F. Boeve, MD,

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  1. Tau Consortium

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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. Behavioral Neurology Of Dementia, Cambridge Univeristy Press, 2009

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  1. NONE

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  1. NONE

Research Support, Commercial Entities:

  1. Grant support as an investigator in clinical trials funded by (1) Cephalon, Inc., 2009-2012, (2) Allon Therapeutics, Inc., 2010-2013; and (3) GE Healthcare, 2012-present.

Research Support, Government Entities:

  1. National Institute on Aging [P50 AG016574 (2009-present), U01 AG006786 (2009-present), RO1 AG032306 (2010-present) and RO1 AG041797 (2012-present)

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  1. NONE

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  1. Mangurian Foundation, 2011-present

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  1. NONE

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Dennis W. Dickson, MD,

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  1. Neotope, South San Francisco

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  1. Editorial board member of: American Journal of Pathology, Journal of Neuropathology and Experimental Neurology, Brain Pathology, Neurobiology of Aging, Annals of Neurology, Neuropathology, International Journal of Clinical and Experimental Pathology.

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  1. NONE

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  1. NONE

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  1. P50-AG16574, P50-NS72187, P01-AG17216, P01- AG03949, R01-AG15866

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  1. NONE

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  1. Cure PSP/Society for PSP

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and Rosa Rademakers, PhDcorresponding author

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  1. Patents held: 'Detecting and Treating Dementia, 12/302,691 (2008) and 'Methods and Materials for Detecting and Treating Dementia' 12/413,869 (2009) Patent on Identification of repeat expansions in C9ORF72

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  1. Received funding from NIH grant P50AG16574 (PI on Project 2 (2007-present); RO1 NS065782-01 (PI, 2009- present); R01 NS080882 (PI, 2012 - present); RO1 AG26251- 03A1 (Coinvestigator, 2009- present); R01 NS076471 (2013 - present); Udall NS72187 (2012-present PI Project 1).

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  1. NONE

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  1. PI on grant from the Amyotrophic Lateral Sclerosis Association (ALSA) (2009-2011) PI on a grant from CurePSP (2009-2011) PI on a grant from the ALS Therapy Alliance (2011-now) PI on grant from the Consortium for Frontotemporal dementia (CFR)(2010-present)

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Abstract

Objective:

To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.

Methods:

A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.

Results:

We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.

Conclusions:

Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) have been described in patients with phenotypic heterogeneity.1,2 They are the major genetic cause of disease in patients with motor neuron disease (MND) and frontotemporal dementia (FTD), but they have also been reported in patients clinically diagnosed with memory disorders, and patients presenting with parkinsonism or psychosis.3 It is currently unknown which modifiers determine its variable disease onset, progression, and other manifestations. Recently, however, evidence pointed toward an oligogenic pathogenesis of MNDs.4 In addition, more than 20 patients have been reported with both C9ORF72 expansions and a mutation in another MND- and/or FTD-associated gene.57 A large cohort of cases with known mutations would be ideal to investigate whether an oligogenic disease model could explain the pleiotropy detected in patients with C9ORF72 expansions. We therefore assessed the frequency of these expansions in a heterogeneous cohort of 334 subjects previously found to carry pathogenic mutations in genes associated with neurodegenerative diseases.

METHODS

Subject selection.

Two study cohorts were analyzed for C9ORF72 repeat expansions. Our initial study cohort consisted of 149 probands with mutations in genes known to be associated with a spectrum of neurodegenerative diseases (table 1). These subjects were of North American descent and obtained through the Mayo Clinic (n = 84), University of Western Ontario (n = 3), University of British Columbia (n = 12), University of Texas Southwestern Medical Center (n = 2), University of California (n = 16), The David Geffen School of Medicine at University of California (n = 2), Northwestern University Feinberg School of Medicine (n = 7, E.H.B.), Drexel University College of Medicine (n = 3), Robarts Research Institute (n = 5), Banner Sun Health Research Institute (n = 4), Coriell Research Institute (n = 8), and Harvard Brain Bank (n = 3).

Table 1
Baseline characteristics

Based on the identification of C9ORF72 repeat expansions in progranulin (GRN) and microtubule-associated protein tau (MAPT) mutation carriers in our initial study cohort, we selected a follow-up cohort with additional GRN and MAPT mutation carriers. This follow-up cohort consisted of 102 family members of probands from our initial study cohort, and 83 subjects from 68 new families of North American and Italian origin. These latter families were provided by other collaborators at IRCCS Istituto Centro San Giovanni di Dio–Fatebenefratelli (n = 68), University of Pennsylvania School of Medicine (n = 3), Northwestern University Feinberg School of Medicine (n = 2, M.M.), National Institute of Neurological Disorders and Stroke and NIH (n = 3), and University of Washington School of Medicine (n = 7).

Standard protocol approvals, registrations, and patient consents.

All subjects agreed to be in the study, and biological samples were obtained after informed consent with ethical committee approval from the respective institutions.

Genetic analysis.

The GGGGCC repeat in C9ORF72 was assessed using a 2-step protocol.1 Briefly, genomic DNA was PCR-amplified with genotyping primers and one fluorescently labeled primer, followed by fragment length analysis on an ABI3730 DNA analyzer (Applied Biosystems, Foster City, CA) and visualized using GeneMapper v4.0 software (Applied Biosystems). For individuals who were shown to be homozygous for C9ORF72 repeats, we performed a repeat-primed PCR, and PCR products were analyzed with an ABI3730 DNA Analyzer and GeneMapper software. A characteristic stutter pattern was considered evidence of a C9ORF72 repeat expansion.

Southern blot.

Southern blotting was performed as described by DeJesus-Hernandez et al.,1 with minor modifications. DNA was isolated from frozen frontal cortex, temporal cortex, and cerebellum. A total of 10 µg of genomic DNA was digested with XbaI, and electrophoresed in an agarose gel. DNA was then transferred to a positively charged nylon membrane (Roche, Penzberg, Germany.) and cross-linked by UV irradiation. After prehybridization in digoxigenin (DIG) EasyHyb solution (Roche), hybridization with a DIG-labeled probe in hybridization solution was performed. Anti-DIG antibody (1:10,000; Roche) was used to detect the probe, which was subsequently visualized with CDP-star substrate (Roche) on X-ray film after an exposure of 30 to 60 minutes.

Immunohistochemistry.

Immunohistochemistry was performed for 3 patients in a blinded fashion, including patient F with double mutations, and for 2 patients from our initial study cohort with only GRN mutations (p.Thr382SerfsX30, c.IVS1+1G>A). Immunohistochemistry for TAR DNA-binding protein 43 (TDP-43) (1:2,500, rabbit polyclonal, Mayo Clinic),8 repeat-associated non-ATG translation peptides (C9RANT, Rb5823, 1:5,000),9 and p62 (1:1,000, lck ligand; BD Bioscience, Franklin Lakes, NJ) was performed on 5-µm-thick sections from the frontal cortex, hippocampus, and cerebellum. These sections were cut from formalin-fixed paraffin-embedded blocks, deparaffinized in xylene, rehydrated in a graded series of ethanol, and washed in distilled water. DAKO Autostainer Plus (DAKO, Carpinteria, CA) and DAKO EnVision+ System–horseradish peroxidase (diaminobenzidine) were used to process stains. To block nonspecific binding, normal goat serum (1:20 in Tris-buffered saline and Tween 20; Sigma, St. Louis, MO) was added to slides before the primary antibody.

RESULTS

Within our initial study cohort of 149 subjects with known pathogenic mutations in neurodegenerative disease genes, we identified 3 individuals with an additional C9ORF72 repeat expansion (2.0%). These expansions were present in 2 subjects with a GRN mutation (p.C466LfsX46 [c.1395_1396insC], p.C31LfsX35 [c.90_91insCTGC]) and in one subject with a MAPT mutation (p.P301L [c.902C>T]). In our follow-up cohort of 185 subjects with GRN or MAPT mutations, we detected another individual with both a GRN mutation (p.R493X [c.1477C>T]) and a C9ORF72 repeat expansion (0.5%).

In total, we therefore identified double mutations in 4 of 334 subjects (1.2%) or 4 of 217 families (1.8%) studied. The C9ORF72 repeat expansions were present in 3 of 204 subjects from our GRN subgroup (1.5% [or 2.0% of 152 GRN families]), and in 1 of 94 subjects from our MAPT subgroup (1.1% [or 3.3% of 30 MAPT families]). Importantly, these subjects with double mutations all showed a behavioral phenotype, and they did not demonstrate signs of MND. Furthermore, our subjects with double mutations appeared to be relatively young when they presented with behavioral impairment (53 years or younger; table 2), as compared with the mean of our initial and follow-up cohorts (56 and 58 years; table 1). All subjects with double mutations had a positive family history for dementia, and interestingly, 2 of 4 of these subjects had family members with MND (50%). Chromatograms and electropherograms of identified subjects are displayed in figure 1, and their pedigrees are shown in figure e-1 on the Neurology® Web site at www.neurology.org. DNA of relatives was unavailable; therefore, cosegregation of the mutations in families could not be assessed.

Table 2
Clinical characteristics of subjects with 2 mutations
Figure 1
Chromatograms and electropherograms of identified subjects

Brain autopsy material, however, was available for one of the identified subjects (F). We obtained DNA from the frontal cortex, temporal cortex, and cerebellum, and performed a Southern blot (in duplicate). Patient F clearly demonstrated an expanded repeat (figure 2), as shown by a smear of high-molecular-weight bands, suggestive for somatic repeat instability.1 The longest repeat expansion of this double mutant was present in the frontal cortex and was estimated to be approximately 23 kb in size, bearing more than 3,000 hexanucleotide repeats.

Figure 2
Southern blot of patient F

Immunohistochemistry was also performed for patient F and 2 control patients with only GRN mutations (figure 3). Patient F showed type A TDP-43 pathology, including neuronal cytoplasmic inclusions and neuritic pathology. In addition, p62 and C9RANT immunohistochemistry showed many neuronal cytoplasmic inclusions, consistent with a mutation in C9ORF72. Blinded investigations of all 3 patients successfully identified the double mutant; whereas all patients demonstrated type A neuronal TDP-43 inclusions,10,11 only patient F showed these inclusions in combination with C9RANT immunoreactivity, and ubiquitin-positive, TDP-43–negative, neuronal cytoplasmic inclusions in the cerebellum, which have been shown to be unique for C9ORF72 repeat expansion carriers.9,12,13 Patient F, therefore, demonstrated mixed pathology with characteristics of both GRN mutations and C9ORF72 expansions.

Figure 3
Neuropathology of patient F

DISCUSSION

In our present study, we discovered C9ORF72 repeat expansions in 4 of 217 families with previously identified mutations in neurodegenerative disease genes. Since the identification of C9ORF72 expansions,1,2 researchers all over the world have reported case series with expansion frequencies.5 On average, these expansions appear to account for 34% of familial MND cases and 26% of familial FTD cases.5 They have, however, also been detected in control subjects; for instance, they were present in 4 of 4,368 control subjects of American and Italian descent.5 Hence, the expansion frequency is significantly higher in our study population than in control subjects of the same origin (1.8% vs 0.1%: p value = 0.0003, Fisher exact test). To date, the sizes of C9ORF72 repeat expansions in brain are largely unknown. Southern blots have proven to be challenging, and good-sized well-characterized cohorts have not been assessed to determine expansion sizes in brain. A recent study did investigate 57 patients with a range of neurodegenerative diseases, and demonstrated great variability in repeat sizes and smear morphologies, but this study focused on blood.14 Thus far, brain tissues of only a few patients have been investigated, demonstrating sizes between approximately 600 and 4,000 repeats.1,1420 We were able to perform a Southern blot for one of our double mutation carriers, patient F, and detected more than 3,000 hexanucleotide repeats. Our findings therefore indicate that this double mutation carrier has a long repeat expansion, in the same range as other patients with C9ORF72 expansions.

The function of C9ORF72 is presently unknown, although recent reports have suggested that C9ORF72 belongs to a group of DENN (differentially expressed in normal and neoplasia) proteins, which are GEFs (guanosine diphosphate/guanosine triphosphate exchange factors) that activate Rab-GTPase switches and regulate vesicular trafficking processes.21,22 Consequently, repeat expansions in C9ORF72 could result in a loss of function and impair these processes. However, an RNA-mediated gain-of-function mechanism could also contribute to disease due to generation of toxic RNA foci.1 Furthermore, recently it was revealed that transcripts of patients with C9ORF72 repeat expansions are also prone to non-ATG translation.9,13 This unconventional method of translation can cause an accumulation of poly(glycine-proline), poly(glycine-alanine), or poly(glycine-arginine) peptides in neurons throughout the CNS, and result in neuropathology specific to C9ORF72-associated MND and/or FTD.9 In our present study, we have shown that one of our subjects with double mutations, patient F, exhibited C9RANT immunoreactivity, consistent with these novel reports. Patient F also harbored ubiquitin-positive, TDP-43–negative, neuronal cytoplasmic inclusions in the cerebellum, which have been shown to be typical for C9ORF72 repeat expansions.12 In addition, patient F demonstrated TDP-43 type A pathology, characteristic for GRN mutations3,10,11,23; thus, this double mutation carrier displayed pathology distinctive for both C9ORF72 expansions and GRN mutations.

Interestingly, 2 patients have already been described with both C9ORF72 repeat expansions and a GRN variant (p.Y294C),24 or a MAPT variant (p.A239T).6 The p.Y294C GRN variant is novel, and has not been detected in other patients or in controls; it was present in a patient with behavioral variant FTD and it is predicted to be damaging.24 The p.A239T MAPT variant was also identified in a patient with behavioral variant FTD.6 She had 2 brothers with C9ORF72 expansions without the MAPT variant, who demonstrated signs of MND. The index case showed mixed pathology with both tauopathy and ubiquitin-positive, TDP-43–negative, neuronal cytoplasmic inclusions in the cerebellum. Nonetheless, accumulation of tau has also been reported in patients with only C9ORF72 expansions, and this accumulation could have resulted from disrupted protein degradation that favors accumulation of multiple different proteins, including tau.25 Although the pathogenicity of the p.Y294C GRN variant and the p.A239T MAPT variant are not entirely clear, the 4 subjects that we identified with C9ORF72 expansions do harbor well-known pathogenic FTD-associated mutations. In tables e-1 and e-2, we have provided a detailed overview of more than 80 families carrying these relatively common mutations. Worldwide, the p.C466LfsX46 mutation accounts for 0.4% of all families with GRN mutations, the p.R493X mutation accounts for 18.6%, and the p.C31LfsX35 mutation accounts for 2.6%; the p.P301L mutation is present in 23.9% of families with MAPT mutations (http://www.molgen.ua.ac.be/FTDmutations/). Therefore, these 4 mutations are frequently detected, and are responsible for approximately 22% of patients with GRN mutations and approximately 24% of patients with MAPT mutations.

Phenotypes of C9ORF72 repeat expansion carriers, in general, appear to differ from patients with mutations in GRN or MAPT.2630 It was shown that age at onset is earlier in patients with C9ORF72 expansions compared to patients with GRN mutations,2629 but later compared to patients with MAPT mutations.2729 Moreover, MND is frequently detected in patients with C9ORF72 expansions, whereas signs of MND are scarce in patients with GRN or MAPT mutations.26,2830 Behavioral variant FTD is the predominant phenotype of all 3 groups; primary progressive aphasia and corticobasal syndrome phenotypes are rare in patients with C9ORF72 expansions, and are more frequently detected in patients with GRN or MAPT mutations.26,29

The co-occurrence of C9ORF72 expansions and mutations in GRN or MAPT in patients with FTD could have several explanations. First, it could be argued that only C9ORF72 expansions are pathogenic, and that the GRN or MAPT mutations are rare benign variants or mere risk factors. This explanation, however, is not supported by ample studies that have revealed a strong association with FTD and indicated that they are definitely disease-causing mutations (tables e-1 and e-2). Second, it is possible that C9ORF72 expansions are not sufficient to develop disease, and that an additional mutation or environmental exposure is needed. This would provide an explanation for the increased frequency of C9ORF72 repeat expansions in cases with other genetic mutations. It is also in accordance with studies that have detected C9ORF72 expansions in control subjects,5 and with studies that reported incomplete or age-dependent penetrance; approximately 50% of expansion carriers were clinically symptomatic by an age of 48 to 58 years, and almost full penetrance was seen at an age of 75 to 80 years.27,31,32 This variable penetrance could be caused by differences in repeat sizes: long repeat sizes may represent clear pathogenic mutations, whereas intermediate sizes may act as risk factors that require a second factor, either genetic or environmental, to cause disease. Our current findings, however, oppose this explanation, while Southern blotting of one of our subjects with double mutations, patient F, revealed a relatively long repeat expansion, comparable to a patient carrying only a C9ORF72 repeat expansion. An age-dependent penetrance has also been reported for GRN, with only 50% of mutation carriers affected by the age of 60 years, and 90% of carriers affected at 70 years,33 comparable to C9ORF72. The penetrance is more than 95% for MAPT.34 It is therefore possible that one of the mutations observed in our double mutation carriers has not yet reached penetrance, and that the current symptoms are solely caused by the other mutation. Finally, it could be hypothesized that both C9ORF72 expansions and GRN or MAPT mutations are pathogenic, that each of these mutations independently causes disease, but that they act as disease modifiers when they co-occur. If we compare the mean age at which symptoms of behavioral impairment occurred between our double mutation carriers (mean: 48.8 ± 3.0, n = 4) and the remainder of our study population (mean: 57.0 ± 0.73, n = 235), then a one-tailed nonparametric Mann-Whitney test results in a p value of 0.0357. Because of the relatively small number of double mutation carriers, this difference is borderline significant, but there is clearly a tendency toward an earlier age at onset. Apart from this relatively young age at onset, all of our patients with double mutations developed signs of behavioral impairment without MND, whereas combinations of C9ORF72 repeat expansions with MND-associated mutations in TARDBP (TAR DNA-binding protein), FUS/TLS (fused in sarcoma/translated in liposarcoma), and SOD1 (superoxide dismutase 1) have previously been detected in patients with MND without FTD.4 However, numerous C9ORF72 expansion carriers without a second mutation in a known dementia gene also developed a pure behavioral variant FTD phenotype. In the future, detailed investigations of multiple patients in families carrying double mutations will be critical to determine the contribution of each mutation to disease.

While previous studies have provided evidence for an oligogenic basis of MND,4 our present findings demonstrate that oligogenicity is not confined to MNDs, and that double mutations can be present in patients with FTD as well. Thus, it is important to realize that patients already diagnosed with mutations in FTD/MND-associated genes could also harbor more recently discovered C9ORF72 repeat expansions, and that they should not be excluded from further tests, which is also highly relevant for genetic counseling, both of patients and of their (unaffected) family members.

Supplementary Material

Data Supplement:

GLOSSARY

C9ORF72
chromosome 9 open reading frame 72
DIG
digoxigenin
FTD
frontotemporal dementia
GRN
progranulin
MAPT
microtubule-associated protein tau
MND
motor neuron disease
TDP-43
TAR DNA-binding protein 43

Footnotes

Supplemental data at www.neurology.org

AUTHOR CONTRIBUTIONS

Marka van Blitterswijk: study concept or design, acquisition of data, analysis or interpretation of data, statistical analysis, drafting the manuscript for content, including writing for content, revising the manuscript for content, including writing for content. Matthew C. Baker, Mariely DeJesus-Hernandez, Melissa E. Murray, Nicola J. Rutherford, Patricia E. Brown, and Thomas Ravenscroft: acquisition of data, analysis or interpretation of data. Roberta Ghidoni, Luisa Benussi, Elizabeth Finger, Ging-Yuek R. Hsiung, Brendan J. Kelley, Bianca Mullen, Peter E.A. Ash, Kevin F. Bieniek, Kimmo J. Hatanpaa, Anna Karydas, Elisabeth McCarty Wood, Giovanni Coppola, Eileen H. Bigio, Carol Lippa, Michael J. Strong, Thomas G. Beach, David S. Knopman, Edward D. Huey, Marsel Mesulam, Thomas Bird, Charles L. White III, Andrew Kertesz, Dan H. Geschwind, and Vivianna M. Van Deerlin: contribution of vital reagents/tools/patients, revising the manuscript for content, including writing for content. Ronald C. Petersen, Giuliano Binetti, Bruce L. Miller, Leonard Petrucelli, Zbigniew K. Wszolek, Kevin B. Boylan, Neill R. Graff-Radford, Ian R. Mackenzie, Bradley F. Boeve, and Dennis W. Dickson: revising the manuscript for content, including writing for content, contribution of vital reagents/tools/patients, obtaining funding. Rosa Rademakers: study concept or design, acquisition of data, analysis or interpretation of data, drafting the manuscript for content, including writing for content, revising the manuscript for content, including writing for content, study supervision or coordination, obtaining funding.

STUDY FUNDING

This work was funded by NIH grants R01 NS080882, R01 NS065782, R01 AG026251, P01 AG017586, P50 NS072187, P50 AG 016574, P30 AG13854, P30 AG12300, and U01 AG006786, the ALS Therapy Alliance, the Consortium for Frontotemporal Dementia Research, and Ricerca Corrente Italian Ministry of Health. Dr. Kelley is the Bob and Sandy Heimann Endowed Chair for Alzheimer's Disease Education and Research at the University of Cincinnati.

DISCLOSURE

M. van Blitterswijk and M. Baker report no disclosures. M. DeJesus-Hernandez holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. R. Ghidoni serves on the editorial boards of Frontiers in Bioscience (Managing Editor), Journal of Alzheimer's Disease (Associate Editor), American Journal of Alzheimer's Disease (Associate Editor), American Journal of Neurodegenerative Disease (Senior Editor), International Journal of Clinical and Experimental Medicine, Geriatrics, and Dataset Papers in Medicine. L. Benussi serves on the editorial board of Journal of Alzheimer's Disease (Associate Editor). E. Finger receives research support from the Lawson Health Research Institute, the University of Western Ontario Academic Development Fund, the Hazel Soper Foundation, and the Alzheimer's Society of London and Middlesex. G. Hsiung receives research support from a CIHR clinical genetics investigatorship, from the Alzheimer Society of Canada, and is an investigator in clinical trials sponsored by Baxter, Bristol-Myers Squibb, Genentech, Hoffmann-La Roche, and Pfizer. B. Kelley has served as a consultant to Lilly; has received research support from Novartis and from NIH. M. Murray, N. Rutherford, P. Brown, T. Ravenscroft, B. Mullen, P. Ash, and K. Bieniek report no disclosures. K. Hatanpaa serves as a consultant for Alere Pharmaceuticals, and receives research support from the NIH. A. Karydas and E. McCarty Wood report no disclosures. G. Coppola is funded by NIH/National Institute on Aging (NIA) grant RC1 AG035610, the Consortium for Frontotemporal Dementia Research, the Adelson Medical Research Foundation, the Tau Consortium, and the Easton Consortium. E. Bigio serves on the editorial boards of the Journal of Neuropathology and Experimental Neurology, Acta Neuropathologica, and Brain Pathology. C. Lippa serves on scientific advisory boards for the Association for Frontotemporal Dementias, the Lewy Body Dementia Association, and the Alzheimer's Association (Delaware Valley Chapter); serves as Editor-in-Chief of the American Journal of Alzheimer's Disease and Other Dementias and the editorial boards of Neurology® and Journal of Neuropathology and Experimental Neurology; and has received research support from UCB, Novartis, Elan Corporation, Janssen, Danone, Potamkin Foundation, and the Newmann Foundation. M. Strong reports no disclosures. T. Beach has contractual funding and/or research support from Eli Lilly Pharmaceuticals, Avid Radiopharmaceuticals, Bayer Schering Pharma, GE Healthcare, the National Institute of Neurological Disorders and Stroke (NINDS) and NIA (U24 NS072026 and P30 AG19610), the Arizona Department of Health Services contract 211002, and the Michael J. Fox Foundation for Parkinson's Research, the Arizona Department of Health Services, and the Arizona Biomedical Research Commission. D. Knopman serves as Deputy Editor for Neurology®; serves on a Data Safety Monitoring Board for Lilly Pharmaceuticals, is an investigator in clinical trials sponsored by Janssen Pharmaceuticals, and receives research support from the NIH. E. Huey is supported by the Intramural Program of NIH/NINDS and by NIH/NINDS grant R00 NS060766. M. Mesulam serves on the scientific advisory boards for the Cure Alzheimer Fund and the Association on Frontotemporal Dementia; serves on the editorial boards of Brain, Annals of Neurology, Human Brain Mapping, and Journal of Cognitive Neuroscience; receives royalties from the publication of Principles of Behavioral and Cognitive Neurology (Oxford University Press, 2000); and receives research support from the NIH. T. Bird receives licensing fees from Athena Diagnostics, Inc. C. White III serves as a scientific advisor for the Michael J. Fox Foundation for Parkinson's Research and receives research support from the NIH, the Winspear Family Center for Research on the Neuropathology of Alzheimer's Disease, and the McCune Foundation. A. Kertesz serves on a scientific advisory board for Pfizer Inc.; serves on the editorial boards of Cognitive and Behavioral Neurology and Aphasiology; receives royalties from the publication of The Western Aphasia Battery (Grune and Stratton, 1982); and has received support from the Lawson Research Institute, the American Neurological Society, and the Whitaker professorship. D. Geschwind serves on scientific advisory boards for Autism Speaks, the Alzheimer Research Forum, and the March of Dimes Birth Defects Foundation; serves on the editorial boards of Neuron, Neurogenetics, Neurobiology of Disease, Current Genomics, Biological Psychiatry, Autism Research, Encyclopedia of Autism and Related Disorders, and Biomed Central; may accrue revenue on patents re: peripheral gene expression biomarkers for autism and full biomarkers in Friedreich ataxia; and receives research support from NIH grant R01 AG026938, The Simons Foundation, and the Consortium for Frontotemporal Dementia Research, and has received institutional support from Alzheimer's Disease Research Center of California grant 03-7527. V. Van Deerlin reports no disclosures. R. Petersen chairs a Data Monitoring Committee for Pfizer, Inc. and Janssen Alzheimer Immunotherapy, and is a consultant for GE Healthcare and Elan Pharmaceuticals. He receives royalties from Oxford University Press for Mild Cognitive Impairment. G. Binetti reports no disclosures. B. Miller serves on a scientific advisory board for the Alzheimer's Disease Clinical Study, serves as an Editor for Neurocase, and as an Associate Editor of ADAD; receives royalties from the publication of Behavioral Neurology of Dementia (Cambridge, 2009), Handbook of Neurology (Elsevier, 2009), and The Human Frontal Lobes (Guilford, 2008); serves as board member on the John Douglas French Alzheimer's Foundation and Larry L. Hillblom Foundation; serves as a consultant for Lundbeck Inc., Allon Therapeutics, Inc., TauRx, Ltd., the Tau Consortium, the Consortium for Frontotemporal Research, and Novartis; and receives research support from Novartis, NIH grants P50 AG023501, P01 AG019724, and P50 AG1657303, and the State of California Alzheimer's Center. L. Petrucelli has received support from the Mayo Clinic Foundation, NIH/NIA (R01 AG026251), NIH/NINDS (R01 NS063964-01, R01 NS077402, ES20395-01), Amyotrophic Lateral Sclerosis Association, and the Department of Defense (W81XWH-10-1-0512-1 and W81XWH-09-1-0315AL093108). Z. Wszolek serves as Co-Editor-in-Chief of Parkinsonism and Related Disorders, Regional Editor of the European Journal of Neurology, and on the editorial boards of Neurologia i Neurochirurgia Polska, Advances in Rehabilitation, Medical Journal of the Rzeszow University, and Clinical and Experimental Medical Letters; holds and has contractual rights for receipt of future royalty payments from patents re: a novel polynucleotide involved in heritable Parkinson disease; receives royalties from publishing Parkinsonism and Related Disorders (Elsevier, 2010, 2011, 2012) and the European Journal of Neurology (Wiley-Blackwell, 2010, 2011, 2012); and receives educational grant support from Allergan, Inc., and research support from the NIH/NINDS P50 NS072187, the Mayo Clinic Center for Regenerative Medicine, and the Dystonia Medical Research Foundation. K. Boylan receives research support from the ALS Association, Biogen Idec, Cytokinetics Inc., and Mayo Foundation, and has received research support from Neuraltus Pharmaceuticals, Avanir Pharmaceuticals, and Synapse Biomedical. N. Graff-Radford serves as board member of The Neurologist, serves as a consultant for Codman, and receives research support from Medivation, Janssen, Allon, Forest, Pfizer, and NIA. I. Mackenzie serves on the editorial boards of Journal of Neuroinflammation, Clinical Neuropathology, Acta Neuropathologica, American Journal of Neurodegenerative Disease, and Neurobiology of Aging; and receives research support from the CIHR, the Pacific Alzheimer Research Fund, and Michael Smith Foundation for Health Research. B. Boeve receives royalties from the publication of Behavioral Neurology of Dementia (Cambridge University Press, 2009) and receives research support from Cephalon, Inc., the NIH, and the Alzheimer's Association. D. Dickson serves on the editorial boards of the American Journal of Pathology, Journal of Neuropathology and Experimental Neurology, Brain Pathology, Neurobiology of Aging, Journal of Neurology, Neurosurgery, and Psychiatry, Annals of Neurology, and Neuropathology; is supported by NIH grants (P50 AG16574, P50 NS72187, and P01 AG03949), the Mangurian Foundation, CurePSP, and the Robert E. Jacoby Professorship for Alzheimer's Research. R. Rademakers receives research support from the NIH (R01 NS080882, R01 NS065782, R01 AG026251, P50 NS072187, and P50 AG16574), the ALS Therapy Alliance, and the Consortium for Frontotemporal Degeneration Research. Dr. Rademakers further received honoraria for lectures or educational activities not funded by industry; she serves on the medical advisory board of the Association for Frontotemporal Degeneration, on the board of directors of the International Society for Frontotemporal Dementia, and holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. Go to Neurology.org for full disclosures.

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