This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (118)  • Contact me when this article is cited  Related Content  • Related articles  • Similar articles in this journal  Topic Collections  • Neurology, Other  • Alert me on articles by topic

Power Calculations and Estimates of Sample Size to Detect Treatment Effects

Nick C. Fox, MA, MRCP; Simon Cousens, DipMathStat; Rachael Scahill, MA; Richard J. Harvey, MD, MRCPsych; Martin N. Rossor, MD, FRCP

Arch Neurol. 2000;57:339-344.

Objective  To evaluate the rate of brain atrophy calculated from serial magnetic resonance imaging (MRI) registration as a surrogate marker of disease progression for use in clinical trials in Alzheimer disease (AD).

Methods  Eighteen patients with mild to moderate AD and 18 age-matched normal controls underwent 2 MRI brain scans separated by a 12-month interval. Each individual's later scan was registered to their first scan, and the volume of cerebral tissue loss calculated directly from the registered and subtracted MRI scan pairs. The mean and SD of the rate of brain volume changes were used to estimate the sample sizes that would be needed in a clinical trial with a drug anticipated to modify disease progression by varying degrees. Comparable sample size estimates were performed with data for other methods of monitoring rates of brain atrophy, extracted from published papers.

Results  The mean (SD) rate of brain atrophy for the patients with AD was 2.37% (1.11%) per year, while in the control group it was 0.41% (0.47%) per year. Based on these figures, to have 90% power to detect a drug effect equivalent to a 20% reduction in the rate of atrophy, 207 patients would be needed in each treatment arm. This assumes a 1-year placebo-controlled trial with a 10% patient dropout rate, and that 10% of scan pairs are unusable.

Conclusion  Registration of serial MRI volume images provides a powerful method of quantification of brain atrophy that can be used to monitor progression of AD in clinical trials.

From the Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, Queen Square (Drs Fox, Harvey, and Rossor and Ms Scahill), the Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (Mr Cousens), and the Imperial College School of Science, Technology and Medicine, St Mary's Campus (Dr Rossor), London, England.

RELATED ARTICLES

Methods for Discerning Disease-Modifying Effects in Alzheimer Disease Treatment Trials
Jeffrey A. Kaye
Arch Neurol. 2000;57(3):312-314.
EXTRACT | FULL TEXT  

Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2000;57(3):430-432.
FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Tracking progression in frontotemporal lobar degeneration: Serial MRI in semantic dementia
Rohrer et al.
Neurology 2008;71:1445-1451.
ABSTRACT | FULL TEXT  

Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database
Nestor et al.
Brain 2008;131:2443-2454.
ABSTRACT | FULL TEXT  

Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis
Zivadinov et al.
Neurology 2008;71:136-144.
ABSTRACT | FULL TEXT  

Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons
Liang et al.
Proc. Natl. Acad. Sci. USA 2008;105:4441-4446.
ABSTRACT | FULL TEXT  

Role of imaging techniques in the diagnosis of dementia
O'BRIEN
Br. J. Radiol. 2007;80:S71-S77.
ABSTRACT | FULL TEXT  

Computational anatomical methods as applied to ageing and dementia
THOMPSON and APOSTOLOVA
Br. J. Radiol. 2007;80:S78-S91.
ABSTRACT | FULL TEXT  

Longitudinal imaging in dementia
SCAHILL and FOX
Br. J. Radiol. 2007;80:S92-S98.
ABSTRACT | FULL TEXT  

Disease-modifying therapies for Alzheimer disease: Challenges to early intervention
Cummings et al.
Neurology 2007;69:1622-1634.
ABSTRACT | FULL TEXT  

Quantitative Magnetization Transfer Imaging in Alzheimer Disease
Ridha et al.
Radiology 2007;244:832-837.
ABSTRACT | FULL TEXT  

Correlations Between Apolipoprotein E {epsilon}4 Gene Dose and Whole Brain Atrophy Rates
Chen et al.
Am. J. Psychiatry 2007;164:916-921.
ABSTRACT | FULL TEXT  

Magnetization Transfer Ratio in Alzheimer Disease: Comparison with Volumetric Measurements
Ridha et al.
Am. J. Neuroradiol. 2007;28:965-970.
ABSTRACT | FULL TEXT  

Quantitative MR Imaging in Alzheimer Disease
Ramani et al.
Radiology 2006;241:26-44.
ABSTRACT | FULL TEXT  

Increased rate of whole-brain atrophy over 6 months in early Huntington disease.
Henley et al.
Neurology 2006;67:694-696.
ABSTRACT | FULL TEXT  

Measuring atrophy in Alzheimer disease: A serial MRI study over 6 and 12 months
Schott et al.
Neurology 2005;65:119-124.
ABSTRACT | FULL TEXT  

Focal Decline of Cortical Thickness in Alzheimer's Disease Identified by Computational Neuroanatomy
Lerch et al.
Cereb Cortex 2005;15:995-1001.
ABSTRACT | FULL TEXT  

Clinical effects of A{beta} immunization (AN1792) in patients with AD in an interrupted trial
Gilman et al.
Neurology 2005;64:1553-1562.
ABSTRACT | FULL TEXT  

Effects of A{beta} immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease
Fox et al.
Neurology 2005;64:1563-1572.
ABSTRACT | FULL TEXT  

Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation
Boeve et al.
Brain 2005;128:752-772.
ABSTRACT | FULL TEXT  

Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD
Jack et al.
Neurology 2004;62:591-600.
ABSTRACT | FULL TEXT  

Differential aging of the medial temporal lobe: A study of a five-year change
Raz et al.
Neurology 2004;62:433-438.
ABSTRACT | FULL TEXT  

Alzheimer's Disease: Neuropathologic Findings and Recent Advances in Imaging
Norfray and Provenzale
Am. J. Roentgenol. 2004;182:3-13.
FULL TEXT  

Dementia: One of the Greatest Fears of Aging
Friedenberg
Radiology 2003;229:632-635.
FULL TEXT  

Neuroimaging tools to rate regional atrophy, subcortical cerebrovascular disease, and regional cerebral blood flow and metabolism: consensus paper of the EADC
Frisoni et al.
J. Neurol. Neurosurg. Psychiatry 2003;74:1371-1381.
ABSTRACT | FULL TEXT  

Changes in premorbid brain volume predict Alzheimer's disease pathology
Silbert et al.
Neurology 2003;61:487-492.
ABSTRACT | FULL TEXT  

Imaging-Based Measures of Disease Progression in Clinical Trials of Disease-Modifying Drugs for Alzheimer Disease
Matthews et al.
AJGP 2003;11:146-159.
ABSTRACT | FULL TEXT  

Alzheimer Disease: Current Concepts and Emerging Diagnostic and Therapeutic Strategies
Clark and Karlawish
ANN INTERN MED 2003;138:400-410.
ABSTRACT | FULL TEXT  

Dementia and ageing: Imaging in clinical neuroscience
Good
Br Med Bull 2003;65:159-168.
ABSTRACT | FULL TEXT  

Atrophy rates of entorhinal cortex in AD and normal aging
Du et al.
Neurology 2003;60:481-486.
ABSTRACT | FULL TEXT  

Dynamics of Gray Matter Loss in Alzheimer's Disease
Thompson et al.
J. Neurosci. 2003;23:994-1005.
ABSTRACT | FULL TEXT  

Neuroimaging and Early Diagnosis of Alzheimer Disease: A Look to the Future
Petrella et al.
Radiology 2003;226:315-336.
ABSTRACT | FULL TEXT  

MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD
Jack et al.
Neurology 2003;60:253-260.
ABSTRACT | FULL TEXT  

Biomarkers in Psychotropic Drug Development
Ahmed et al.
AJGP 2002;10:678-686.
ABSTRACT | FULL TEXT  

Seizure-induced neuronal injury: Human data
Duncan
Neurology 2002;59:S15-20.
ABSTRACT | FULL TEXT  

Hat size, brain size, intelligence, and dementia: What morphometry can tell us about brain function and disease
Drachman
Neurology 2002;59:156-157.
FULL TEXT  

Serial brain MRI at 3-6 month intervals as a surrogate marker for Alzheimer's disease
Bradley et al.
Br. J. Radiol. 2002;75:506-513.
ABSTRACT | FULL TEXT  

Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies
Alexander et al.
Am. J. Psychiatry 2002;159:738-745.
ABSTRACT | FULL TEXT  

Temporal Lobe Morphology in Normal Aging and Traumatic Brain Injury
Bigler et al.
Am. J. Neuroradiol. 2002;23:255-266.
ABSTRACT | FULL TEXT  

Hippocampal Atrophy Correlates With Clinical Features of Alzheimer Disease in African Americans
Sencakova et al.
Arch Neurol 2001;58:1593-1597.
ABSTRACT | FULL TEXT  

Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in Dementias
Hsu et al.
J Geriatr Psychiatry Neurol 2001;14:145-166.
ABSTRACT  

Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia
O'Brien et al.
Neurology 2001;56:1386-1388.
ABSTRACT | FULL TEXT  

Premorbid Brain Volume and Dementia
Bigler et al.
Arch Neurol 2001;58:831-833.
FULL TEXT  

Cortical Change in Alzheimer's Disease Detected with a Disease-specific Population-based Brain Atlas
Thompson et al.
Cereb Cortex 2001;11:1-16.
ABSTRACT | FULL TEXT  

Methods for Discerning Disease-Modifying Effects in Alzheimer Disease Treatment Trials
Kaye
Arch Neurol 2000;57:312-314.
FULL TEXT  

Functional brain imaging to identify affected subjects genetically at risk for Alzheimer's disease
Rapoport
Proc. Natl. Acad. Sci. USA 2000;97:5696-5698.
FULL TEXT