Brain Advance Access published online on October 1, 2008
Brain, doi:10.1093/brain/awn234
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Development of methodology for conducting clinical trials in frontotemporal lobar degeneration
1Mayo Clinic, Rochester, MN, 2University of California, San Francisco, San Francisco, CA, 3Mayo Clinic, Scottsdale, AZ, 4Mayo Clinic, Jacksonville, FL, 5University of California Los Angeles, Los Angeles, CA and 6University of Washington, Seattle, WA, USA
Correspondence to:
David S. Knopman, MD, Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester MN 55905, USA E-mail: knopman{at}mayo.edu
To design clinical trials for the frontotemporal lobar degenerations (FTLD), knowledge about measurement of disease progression is needed to estimate power and enable the choice of optimal outcome measures. The aim here was to conduct a multicentre, 1 year replica of a clinical trial in patients with one of four FTLD syndromes, behavioural variant frontotemporal dementia (bvFTD), progressive nonfluent aphasia (PNFA), progressive logopenic aphasia (PLA) and semantic dementia (SMD). Patients with one of the four FTLD syndromes were recruited from five academic medical centres over a 2 year period. Standard operationalized diagnostic criteria were used. In addition to clinical inclusion and exclusion criteria, patients were required to exhibit focal frontal, temporal or insular brain atrophy or dysfunction by neuroimaging. Patients underwent neuropsychological, functional, behavioural, neurological and MR imaging assessment at baseline and approximately 12 months later. Potential outcome measures were examined for their rates of floor and ceiling values at baseline and end of study, their mean changes and variances. The neuropsychological tests were combined into two cognitive composites—one for language functions and the other for executive functions. There were 107 patients who underwent baseline assessment and 78 who completed a follow-up assessment within 10–16 months. Two global measures, the FTLD-modified Clinical Dementia Rating (FTLD-modified CDR) and the Clinical Global Impression of Change (CGIC) demonstrated decline in the majority of patients. Several cognitive measures showed negligible floor or ceiling scores either at baseline or follow-up. Scores declined at follow-up in the majority of patients. The cognitive, executive and combined composites were shown to be sensitive to change across all FTLD syndromes. Patients improved at follow-up on the behavioural scales—the Frontal Behavioural Inventory (22%) and the Neuropsychiatric Inventory (28%)—suggesting that these instruments may not be ideal for clinical trial use. It was feasible to recruit FTLD patients in a simulated multi-centre trial. 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.
Key Words: frontotemporal dementia; clinical trials; neuropsychology
Abbreviations: bvFTD, behavioural variant frontotemporal dementia; CGIC, Clinical Global Impression of Change; FAQ, Functional Activities Questionnaire; FBI, Frontal Behavioral Inventory; FTLD, frontotemporal lobar degenerations; FTLD-CDR, FTLD-specific Clinical Dementia Rating; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; PLA, progressive logopenic aphasia; PNFA, progressive nonfluent aphasia; SMD, semantic dementia
Received March 17, 2008. Revised August 27, 2008. Accepted August 28, 2008.
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