Frontotemporal degeneration: a basis for clinical trials

Summary

Principal Investigator: D Knopman
Abstract: In order to test drugs in patients with tauopathies, knowledge of the natural history of the frontotemporal lobar dementias (FTLD) must be expressed in terms suitable for designing clinical trials. Without valid estimates of change over 6 or 12 months, instruments appropriate for trials and sample sizes for the trials simply cannot be determined. We are proposing a 4 year, multi-site, longitudinal study of patients with FTLD in which we will recruit subjects using standardized criteria. The specific aims of this project are 1) determine the ratio between change and variance in cognitive, behavioral and functional instruments in order to estimate power to detect treatment effects with each instrument in future clinical trials; 2) perform serial MR imaging to determine the magnitude of change and its variance in global and regional frontal or temporal brain volume in order to estimate power to detect treatment effects on brain volume in future clinical trials; 3) develop a composite FTLD-subtype-specific cognitive instrument for use in clinical trials; and 4) determine whether ApoE genotype and tau haplotype are associated with rate of progression on cognitive, behavioral, functional or imaging in FTLD. We propose to involve 3 Alzheimer Disease Centers (Mayo Rochester/Jacksonville, UCLA and Arizona) plus the University of California- San Francisco to recruit 120 patients with FTLD. We shall recruit patients with the behavioral-dysexecutive syndrome of fronto-temporal dementia, patients with semantic dementia, and patients with progressive nonfluent aphasia. Operational criteria for these 3 syndromes have been developed that will meet rigorous standards suitable for clinical trial recruitment. Subjects will be examined with cognitive, behavioral, functional assessments as well as MR imaging at baseline and 12 months. Key outcomes will include estimates of change and its variability over 1 year on MR imaging, change on cognitive tasks including the composite task, and change on functional and behavioral measures. While the study will also develop a wealth of new knowledge about the relationships between cognition, behavior and brain structure in FTLD, the essential product of this study will be the principles underlying a rationale design for trials of drugs for FTLD.
Funding Period: 2003-09-30 - 2009-02-28
more information: NIH RePORT

Top Publications

  1. pmc Patterns of brain atrophy in clinical variants of frontotemporal lobar degeneration
    Po H Lu
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Dement Geriatr Cogn Disord 35:34-50. 2013
  2. pmc Comparison of imaging biomarkers in the Alzheimer Disease Neuroimaging Initiative and the Mayo Clinic Study of Aging
    Jennifer L Whitwell
    Department of Radiology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Arch Neurol 69:614-22. 2012
  3. pmc Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia
    J L Whitwell
    Department of Radiology, Mayo Clinic, Rochester MN 55905, USA
    Neurology 74:1279-87. 2010
  4. pmc Serial MRI and CSF biomarkers in normal aging, MCI, and AD
    P Vemuri
    Aging and Dementia Imaging Research Laboratory, Department of Radiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
    Neurology 75:143-51. 2010
  5. pmc MRS in presymptomatic MAPT mutation carriers: a potential biomarker for tau-mediated pathology
    K Kantarci
    Departmentsof Radiology, Mayo Clinic, Rochester, MN 55905, USA
    Neurology 75:771-8. 2010
  6. pmc Computerized analysis of speech and language to identify psycholinguistic correlates of frontotemporal lobar degeneration
    Serguei V S Pakhomov
    University of Minnesota, Twin Cities, MN, USA
    Cogn Behav Neurol 23:165-77. 2010
  7. pmc Imaging correlates of pathology in corticobasal syndrome
    J L Whitwell
    Department of Radiology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
    Neurology 75:1879-87. 2010
  8. pmc Language and behavior domains enhance the value of the clinical dementia rating scale
    David S Knopman
    Department of Neurology, Mayo Clinic, Rochester, MN, USA
    Alzheimers Dement 7:293-9. 2011
  9. pmc Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics
    Jennifer L Whitwell
    Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
    Brain 135:794-806. 2012
  10. pmc Off-label medication use in frontotemporal dementia
    - Bei Hu
    Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA
    Am J Alzheimers Dis Other Demen 25:128-33. 2010

Scientific Experts

  • D Knopman
  • J L Whitwell
  • K A Josephs
  • Serguei V S Pakhomov
  • S R Lesage
  • B Boeve
  • Neill Graff-Radford
  • Po H Lu
  • Mario F Mendez
  • Richard J Caselli
  • Bruce L Miller
  • R C Petersen
  • Jennifer Molano
  • C R Jack
  • K Kantarci
  • - Bei Hu
  • P Vemuri
  • Dennis Dickson
  • Jennifer Gass
  • Grace J Lee
  • Neill R Graff-Radford
  • Hyun Woo Lee
  • Alex D Leow
  • Jill Shapira
  • Clifford R Jack
  • Joel H Kramer
  • Paul M Thompson
  • George Bartzokis
  • Elvira Jimenez
  • A R Samikoglu
  • V Shane Pankratz
  • R Rademakers
  • M A Bernstein
  • Maria Shiung
  • M L Senjem
  • Glenn Smith
  • L M Shaw
  • M Weiner
  • TANIS FERMAN
  • Ronald Petersen
  • Yonas Geda
  • Michael Silber
  • M C Baker
  • Joseph Parisi
  • Adam L Boxer
  • H J Wiste
  • J Q Trojanowski
  • Kejal Kantarci
  • S D Weigand
  • John Lucas
  • Clifford Jack
  • John Neuhaus
  • Leslie Ross
  • Z K Wszolek
  • P S Aisen
  • Joel Kramer
  • Charles L White
  • Stuart M Pickering-Brown
  • Marsel Mesulam
  • John Gonzalez
  • Matt Baker
  • Ging Yuek Hsiung
  • Howard Feldman
  • Rosa Rademakers
  • Jennifer Adamson
  • Stacey Melquist
  • Sandra Weintraub
  • Ryan Uitti
  • Thomas G Beach
  • Richard Caselli
  • Ian R Mackenzie
  • Bryan Woodruff
  • Ron Petersen
  • Nancy Johnson
  • Eileen Bigio
  • Zbigniew Wszolek
  • Mike Hutton
  • Ashley Cannon
  • Karen Kuntz
  • Richard Crook

Detail Information

Publications24

  1. pmc Patterns of brain atrophy in clinical variants of frontotemporal lobar degeneration
    Po H Lu
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Dement Geriatr Cogn Disord 35:34-50. 2013
    ..Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups...
  2. pmc Comparison of imaging biomarkers in the Alzheimer Disease Neuroimaging Initiative and the Mayo Clinic Study of Aging
    Jennifer L Whitwell
    Department of Radiology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Arch Neurol 69:614-22. 2012
    ..To determine whether magnetic resonance imaging measurements observed in the Alzheimer Disease Neuroimaging Initiative (ADNI) convenience sample differ from those observed in the Mayo Clinic Study of Aging (MCSA) population-based sample...
  3. pmc Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia
    J L Whitwell
    Department of Radiology, Mayo Clinic, Rochester MN 55905, USA
    Neurology 74:1279-87. 2010
    ..To use diffusion tensor imaging (DTI) to assess gray matter and white matter tract diffusion in behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SMD), and progressive nonfluent aphasia (PNFA)...
  4. pmc Serial MRI and CSF biomarkers in normal aging, MCI, and AD
    P Vemuri
    Aging and Dementia Imaging Research Laboratory, Department of Radiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
    Neurology 75:143-51. 2010
    ..Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials...
  5. pmc MRS in presymptomatic MAPT mutation carriers: a potential biomarker for tau-mediated pathology
    K Kantarci
    Departmentsof Radiology, Mayo Clinic, Rochester, MN 55905, USA
    Neurology 75:771-8. 2010
    ..To determine the proton magnetic resonance spectroscopy ((1)H MRS) changes in carriers of microtubule-associated protein (MAPT) mutations in a case-control study...
  6. pmc Computerized analysis of speech and language to identify psycholinguistic correlates of frontotemporal lobar degeneration
    Serguei V S Pakhomov
    University of Minnesota, Twin Cities, MN, USA
    Cogn Behav Neurol 23:165-77. 2010
    ..To evaluate the use of a semiautomated computerized system for measuring speech and language characteristics in patients with frontotemporal lobar degeneration (FTLD)...
  7. pmc Imaging correlates of pathology in corticobasal syndrome
    J L Whitwell
    Department of Radiology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
    Neurology 75:1879-87. 2010
    ..The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS...
  8. pmc Language and behavior domains enhance the value of the clinical dementia rating scale
    David S Knopman
    Department of Neurology, Mayo Clinic, Rochester, MN, USA
    Alzheimers Dement 7:293-9. 2011
    ..The CDRstd does not specifically address language dysfunction or alteration in personality and social behaviors which are prominent in behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA)...
  9. pmc Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics
    Jennifer L Whitwell
    Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
    Brain 135:794-806. 2012
    ..Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level...
  10. pmc Off-label medication use in frontotemporal dementia
    - Bei Hu
    Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA
    Am J Alzheimers Dis Other Demen 25:128-33. 2010
    ..We sought to determine the most commonly used drugs used to treat behavioral variant FTD (bvFTD) in specialized dementia clinics...
  11. pmc Mild cognitive impairment associated with limbic and neocortical Lewy body disease: a clinicopathological study
    Jennifer Molano
    Mayo Clinic, Rochester, MN 55905, USA
    Brain 133:540-56. 2010
    ....
  12. ncbi Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP
    K A Josephs
    Division of Movement Disorders, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
    Neurology 66:41-8. 2006
    ..To examine the relationship between early clinical features, pathologies, and biochemistry of the frontotemporal lobar degenerations (FTLDs), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)...
  13. ncbi Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration
    Jennifer Gass
    Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA
    Hum Mol Genet 15:2988-3001. 2006
    ..Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers...
  14. ncbi A review of the non-Alzheimer dementias
    Bradley F Boeve
    Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Clin Psychiatry 67:1985-2001; discussion 1983-4. 2006
    ..To review the clinical features, neuropathologic features, clinical course, differential diagnosis, evaluation, and management strategies of the primary non-Alzheimer degenerative and prion disorders that cause dementia...
  15. ncbi Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease
    B F Boeve
    Department of Neurology, 6Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Brain 130:2770-88. 2007
    ..Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials...
  16. ncbi Parkinson-related dementias
    Bradley F Boeve
    Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
    Neurol Clin 25:761-81, vii. 2007
    ....
  17. ncbi Longitudinal tracking of FTLD: toward developing clinical trial methodology
    David S Knopman
    Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
    Alzheimer Dis Assoc Disord 21:S58-63. 2007
    ..In addition, a multicenter trial is described in which some aspects of diagnosis and longitudinal measurement in the frontotemporal lobar degenerations are being specifically explored...
  18. pmc Development of methodology for conducting clinical trials in frontotemporal lobar degeneration
    David S Knopman
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Brain 131:2957-68. 2008
    ..There are several candidate outcome measures -- including the FTLD-CDR and the cognitive composites -- that could be used in clinical trials across the spectrum of FTLD...
  19. pmc Brain and ventricular volumetric changes in frontotemporal lobar degeneration over 1 year
    D S Knopman
    Department of Neurology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA
    Neurology 72:1843-9. 2009
    ..Because there is only limited longitudinal imaging data currently available, we measured the rate of change over 1 year of whole brain volume (WBV) and ventricular volume (VV) in patients with FTLD...
  20. pmc Retinal microvascular abnormalities and cognitive decline: the ARIC 14-year follow-up study
    S R Lesage
    University of Maryland Medical Center, Department of Neurology, 22 S Greene St, Baltimore, MD 21201, USA
    Neurology 73:862-8. 2009
    ..To better understand the role of SVD in cognitive function, we investigated the relationship between retinal microvascular abnormalities and longitudinal changes in cognitive function in a community-based study...
  21. pmc Two distinct subtypes of right temporal variant frontotemporal dementia
    K A Josephs
    Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
    Neurology 73:1443-50. 2009
    ..We aimed to determine whether right temporal FTD is a homogeneous clinical, imaging, and pathologic/genetic entity...
  22. ncbi Antemortem diagnosis of frontotemporal lobar degeneration
    David S Knopman
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
    Ann Neurol 57:480-8. 2005
    ..The antemortem consensus diagnosis of FTLD was moderately sensitive and very specific. With experienced clinicians and awareness of the unique manifestations of FTLD, accurate antemortem diagnosis was feasible...