Combining short interval MRI in Alzheimer's disease: Implications for therapeutic trials

J. M. Schott, C. Frost, Jennifer Lynn Whitwell, D. G. MacManus, R. G. Boyes, M. N. Rossor, N. C. Fox

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Cerebral atrophy calculated from serial MRI is a marker of Alzheimer's disease (AD) progression, and a potential outcome measure for therapeutic trials. Reducing within-subject variability in cerebral atrophy rates by acquiring more than two serial scans could allow for shorter clinical trials requiring smaller patient numbers. Forty-six patients with AD and 23 controls each had up to 10 serial MR brain scans over two years. Whole brain atrophy was calculated for each subject from every scan-pair. 708 volumetric MRI scans were acquired: 2199 measures of atrophy were made for patients, and 1182 for controls. A linear mixed model was used to characterise between and within-individual variability. These results were used to investigate the power of combining multiple serial scans in treatment trials of varying lengths. In AD, the mean whole brain atrophy rate was 2.23%/year (95% CI: 1.90-2.56%/year). The linear mixed model was shown to fit the data well and led to a formula (0.992+(0.82/t)2) for the variance of atrophy rates calculated from two scans "t" years apart. Utilising five optimally timed scans with repeat scans at each visit reduced the component of atrophy rate variance attributable to within-subject variability by ∼ 56%, equating to a ∼ 40% sample size reduction (228 vs 387 patients per arm to detect 20% reduction in atrophy rate) in a six-month placebo-controlled trial. This benefit in terms of sample size is relatively reduced in longer trials, although adding extra scanning visits may have benefits when patient drop-outs are accounted for. We conclude that sample sizes required in short interval therapeutic trials using cerebral atrophy as an outcome measure may be reduced if multiple serial MRI is performed.

Original languageEnglish (US)
Pages (from-to)1147-1153
Number of pages7
JournalJournal of Neurology
Volume253
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

Fingerprint

Atrophy
Alzheimer Disease
Sample Size
Therapeutics
Linear Models
Brain
Outcome Assessment (Health Care)
Disease Progression
Placebos
Magnetic Resonance Imaging
Clinical Trials

Keywords

  • Alzheimer's disease
  • MRI
  • Sample size
  • Short interval
  • Trial design

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Schott, J. M., Frost, C., Whitwell, J. L., MacManus, D. G., Boyes, R. G., Rossor, M. N., & Fox, N. C. (2006). Combining short interval MRI in Alzheimer's disease: Implications for therapeutic trials. Journal of Neurology, 253(9), 1147-1153. https://doi.org/10.1007/s00415-006-0173-4

Combining short interval MRI in Alzheimer's disease : Implications for therapeutic trials. / Schott, J. M.; Frost, C.; Whitwell, Jennifer Lynn; MacManus, D. G.; Boyes, R. G.; Rossor, M. N.; Fox, N. C.

In: Journal of Neurology, Vol. 253, No. 9, 09.2006, p. 1147-1153.

Research output: Contribution to journalArticle

Schott, JM, Frost, C, Whitwell, JL, MacManus, DG, Boyes, RG, Rossor, MN & Fox, NC 2006, 'Combining short interval MRI in Alzheimer's disease: Implications for therapeutic trials', Journal of Neurology, vol. 253, no. 9, pp. 1147-1153. https://doi.org/10.1007/s00415-006-0173-4
Schott, J. M. ; Frost, C. ; Whitwell, Jennifer Lynn ; MacManus, D. G. ; Boyes, R. G. ; Rossor, M. N. ; Fox, N. C. / Combining short interval MRI in Alzheimer's disease : Implications for therapeutic trials. In: Journal of Neurology. 2006 ; Vol. 253, No. 9. pp. 1147-1153.
@article{c95cd4ec423a4d839e3ae45073571ee2,
title = "Combining short interval MRI in Alzheimer's disease: Implications for therapeutic trials",
abstract = "Cerebral atrophy calculated from serial MRI is a marker of Alzheimer's disease (AD) progression, and a potential outcome measure for therapeutic trials. Reducing within-subject variability in cerebral atrophy rates by acquiring more than two serial scans could allow for shorter clinical trials requiring smaller patient numbers. Forty-six patients with AD and 23 controls each had up to 10 serial MR brain scans over two years. Whole brain atrophy was calculated for each subject from every scan-pair. 708 volumetric MRI scans were acquired: 2199 measures of atrophy were made for patients, and 1182 for controls. A linear mixed model was used to characterise between and within-individual variability. These results were used to investigate the power of combining multiple serial scans in treatment trials of varying lengths. In AD, the mean whole brain atrophy rate was 2.23{\%}/year (95{\%} CI: 1.90-2.56{\%}/year). The linear mixed model was shown to fit the data well and led to a formula (0.992+(0.82/t)2) for the variance of atrophy rates calculated from two scans {"}t{"} years apart. Utilising five optimally timed scans with repeat scans at each visit reduced the component of atrophy rate variance attributable to within-subject variability by ∼ 56{\%}, equating to a ∼ 40{\%} sample size reduction (228 vs 387 patients per arm to detect 20{\%} reduction in atrophy rate) in a six-month placebo-controlled trial. This benefit in terms of sample size is relatively reduced in longer trials, although adding extra scanning visits may have benefits when patient drop-outs are accounted for. We conclude that sample sizes required in short interval therapeutic trials using cerebral atrophy as an outcome measure may be reduced if multiple serial MRI is performed.",
keywords = "Alzheimer's disease, MRI, Sample size, Short interval, Trial design",
author = "Schott, {J. M.} and C. Frost and Whitwell, {Jennifer Lynn} and MacManus, {D. G.} and Boyes, {R. G.} and Rossor, {M. N.} and Fox, {N. C.}",
year = "2006",
month = "9",
doi = "10.1007/s00415-006-0173-4",
language = "English (US)",
volume = "253",
pages = "1147--1153",
journal = "Journal of Neurology",
issn = "0340-5354",
publisher = "D. Steinkopff-Verlag",
number = "9",

}

TY - JOUR

T1 - Combining short interval MRI in Alzheimer's disease

T2 - Implications for therapeutic trials

AU - Schott, J. M.

AU - Frost, C.

AU - Whitwell, Jennifer Lynn

AU - MacManus, D. G.

AU - Boyes, R. G.

AU - Rossor, M. N.

AU - Fox, N. C.

PY - 2006/9

Y1 - 2006/9

N2 - Cerebral atrophy calculated from serial MRI is a marker of Alzheimer's disease (AD) progression, and a potential outcome measure for therapeutic trials. Reducing within-subject variability in cerebral atrophy rates by acquiring more than two serial scans could allow for shorter clinical trials requiring smaller patient numbers. Forty-six patients with AD and 23 controls each had up to 10 serial MR brain scans over two years. Whole brain atrophy was calculated for each subject from every scan-pair. 708 volumetric MRI scans were acquired: 2199 measures of atrophy were made for patients, and 1182 for controls. A linear mixed model was used to characterise between and within-individual variability. These results were used to investigate the power of combining multiple serial scans in treatment trials of varying lengths. In AD, the mean whole brain atrophy rate was 2.23%/year (95% CI: 1.90-2.56%/year). The linear mixed model was shown to fit the data well and led to a formula (0.992+(0.82/t)2) for the variance of atrophy rates calculated from two scans "t" years apart. Utilising five optimally timed scans with repeat scans at each visit reduced the component of atrophy rate variance attributable to within-subject variability by ∼ 56%, equating to a ∼ 40% sample size reduction (228 vs 387 patients per arm to detect 20% reduction in atrophy rate) in a six-month placebo-controlled trial. This benefit in terms of sample size is relatively reduced in longer trials, although adding extra scanning visits may have benefits when patient drop-outs are accounted for. We conclude that sample sizes required in short interval therapeutic trials using cerebral atrophy as an outcome measure may be reduced if multiple serial MRI is performed.

AB - Cerebral atrophy calculated from serial MRI is a marker of Alzheimer's disease (AD) progression, and a potential outcome measure for therapeutic trials. Reducing within-subject variability in cerebral atrophy rates by acquiring more than two serial scans could allow for shorter clinical trials requiring smaller patient numbers. Forty-six patients with AD and 23 controls each had up to 10 serial MR brain scans over two years. Whole brain atrophy was calculated for each subject from every scan-pair. 708 volumetric MRI scans were acquired: 2199 measures of atrophy were made for patients, and 1182 for controls. A linear mixed model was used to characterise between and within-individual variability. These results were used to investigate the power of combining multiple serial scans in treatment trials of varying lengths. In AD, the mean whole brain atrophy rate was 2.23%/year (95% CI: 1.90-2.56%/year). The linear mixed model was shown to fit the data well and led to a formula (0.992+(0.82/t)2) for the variance of atrophy rates calculated from two scans "t" years apart. Utilising five optimally timed scans with repeat scans at each visit reduced the component of atrophy rate variance attributable to within-subject variability by ∼ 56%, equating to a ∼ 40% sample size reduction (228 vs 387 patients per arm to detect 20% reduction in atrophy rate) in a six-month placebo-controlled trial. This benefit in terms of sample size is relatively reduced in longer trials, although adding extra scanning visits may have benefits when patient drop-outs are accounted for. We conclude that sample sizes required in short interval therapeutic trials using cerebral atrophy as an outcome measure may be reduced if multiple serial MRI is performed.

KW - Alzheimer's disease

KW - MRI

KW - Sample size

KW - Short interval

KW - Trial design

UR - http://www.scopus.com/inward/record.url?scp=33749442924&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749442924&partnerID=8YFLogxK

U2 - 10.1007/s00415-006-0173-4

DO - 10.1007/s00415-006-0173-4

M3 - Article

C2 - 16998650

AN - SCOPUS:33749442924

VL - 253

SP - 1147

EP - 1153

JO - Journal of Neurology

JF - Journal of Neurology

SN - 0340-5354

IS - 9

ER -