Frontotemporal degeneration: a basis for clinical trials
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
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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...
- Comparison of imaging biomarkers in the Alzheimer Disease Neuroimaging Initiative and the Mayo Clinic Study of AgingJennifer 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...
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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)...
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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...
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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...
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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)...
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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...
- Language and behavior domains enhance the value of the clinical dementia rating scaleDavid 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)...
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Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
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Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA
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Mayo Clinic, Rochester, MN 55905, USA
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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)...
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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...
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Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA
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Department of Neurology, 6Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Neurol Clin 25:761-81, vii. 2007....
- Longitudinal tracking of FTLD: toward developing clinical trial methodologyDavid 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...
- Development of methodology for conducting clinical trials in frontotemporal lobar degenerationDavid 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...
- Brain and ventricular volumetric changes in frontotemporal lobar degeneration over 1 yearD 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...
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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...
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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...
- Antemortem diagnosis of frontotemporal lobar degenerationDavid 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...