Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment

M. Lorenzi, M. Donohue, D. Paternicò, C. Scarpazza, S. Ostrowitzki, O. Blin, E. Irving, G. B. Frisoni

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed.

Original languageEnglish
JournalNeurobiology of Aging
Volume31
Issue number8
DOIs
Publication statusPublished - Aug 2010

Fingerprint

Positron-Emission Tomography
Biomarkers
Clinical Trials
Sample Size
Pharmaceutical Preparations
Fluorodeoxyglucose F18
Alzheimer Disease
Outcome Assessment (Health Care)
Cognitive Dysfunction
Amyloid
Neuroimaging
Atrophy
Cerebrospinal Fluid
Dementia
Magnetic Resonance Spectroscopy
N-methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole

Keywords

  • Clinical trials
  • Conversion
  • Enrichment
  • Marker disease
  • Mild cognitive impairment

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment. / Lorenzi, M.; Donohue, M.; Paternicò, D.; Scarpazza, C.; Ostrowitzki, S.; Blin, O.; Irving, E.; Frisoni, G. B.

In: Neurobiology of Aging, Vol. 31, No. 8, 08.2010.

Research output: Contribution to journalArticle

Lorenzi, M. ; Donohue, M. ; Paternicò, D. ; Scarpazza, C. ; Ostrowitzki, S. ; Blin, O. ; Irving, E. ; Frisoni, G. B. / Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment. In: Neurobiology of Aging. 2010 ; Vol. 31, No. 8.
@article{d305efa6867c43548fb35233829212f6,
title = "Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment",
abstract = "Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed.",
keywords = "Clinical trials, Conversion, Enrichment, Marker disease, Mild cognitive impairment",
author = "M. Lorenzi and M. Donohue and D. Paternic{\`o} and C. Scarpazza and S. Ostrowitzki and O. Blin and E. Irving and Frisoni, {G. B.}",
year = "2010",
month = "8",
doi = "10.1016/j.neurobiolaging.2010.04.036",
language = "English",
volume = "31",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment

AU - Lorenzi, M.

AU - Donohue, M.

AU - Paternicò, D.

AU - Scarpazza, C.

AU - Ostrowitzki, S.

AU - Blin, O.

AU - Irving, E.

AU - Frisoni, G. B.

PY - 2010/8

Y1 - 2010/8

N2 - Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed.

AB - Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed.

KW - Clinical trials

KW - Conversion

KW - Enrichment

KW - Marker disease

KW - Mild cognitive impairment

UR - http://www.scopus.com/inward/record.url?scp=77954028812&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954028812&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2010.04.036

DO - 10.1016/j.neurobiolaging.2010.04.036

M3 - Article

VL - 31

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

IS - 8

ER -