Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials

Adam S. Fleisher, Abhinay D. Joshi, Karen L. Sundell, Yun Fei Chen, Sara Kollack-Walker, Ming Lu, Sherry Chen, Michael D. Devous, John Seibyl, Kenneth Marek, Eric R. Siemers, Mark A. Mintun

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Introduction: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. Methods: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. Results: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. Discussion: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
DOIs
StateAccepted/In press - 2017

Fingerprint

solanezumab
Positron-Emission Tomography
Cerebellum
Placebos
Sample Size
Therapeutics
Amyloid
Dementia
Alzheimer Disease
White Matter
florbetapir

Keywords

  • Alzheimer's disease
  • Disease course
  • Florbetapir
  • Growth mixture model
  • Reference region
  • Serial PET imaging
  • Solanezumab
  • Trajectory

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials. / Fleisher, Adam S.; Joshi, Abhinay D.; Sundell, Karen L.; Chen, Yun Fei; Kollack-Walker, Sara; Lu, Ming; Chen, Sherry; Devous, Michael D.; Seibyl, John; Marek, Kenneth; Siemers, Eric R.; Mintun, Mark A.

In: Alzheimer's and Dementia, 2017.

Research output: Contribution to journalArticle

Fleisher, AS, Joshi, AD, Sundell, KL, Chen, YF, Kollack-Walker, S, Lu, M, Chen, S, Devous, MD, Seibyl, J, Marek, K, Siemers, ER & Mintun, MA 2017, 'Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials', Alzheimer's and Dementia. https://doi.org/10.1016/j.jalz.2017.02.009
Fleisher, Adam S. ; Joshi, Abhinay D. ; Sundell, Karen L. ; Chen, Yun Fei ; Kollack-Walker, Sara ; Lu, Ming ; Chen, Sherry ; Devous, Michael D. ; Seibyl, John ; Marek, Kenneth ; Siemers, Eric R. ; Mintun, Mark A. / Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials. In: Alzheimer's and Dementia. 2017.
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abstract = "Introduction: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. Methods: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. Results: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85{\%} to 90{\%}. Discussion: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.",
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AU - Fleisher, Adam S.

AU - Joshi, Abhinay D.

AU - Sundell, Karen L.

AU - Chen, Yun Fei

AU - Kollack-Walker, Sara

AU - Lu, Ming

AU - Chen, Sherry

AU - Devous, Michael D.

AU - Seibyl, John

AU - Marek, Kenneth

AU - Siemers, Eric R.

AU - Mintun, Mark A.

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N2 - Introduction: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. Methods: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. Results: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. Discussion: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.

AB - Introduction: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. Methods: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. Results: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. Discussion: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.

KW - Alzheimer's disease

KW - Disease course

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KW - Growth mixture model

KW - Reference region

KW - Serial PET imaging

KW - Solanezumab

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