The effect of diagnostic criteria on outcome measures in preclinical and prodromal Alzheimer's disease: Implications for trial design

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Abstract

Introduction

We investigated the influence of different inclusion criteria for preclinical and prodromal Alzheimer's disease (AD) on changes in biomarkers and cognitive markers and on trial sample size estimates.

Methods

We selected 522 cognitively normal subjects and 872 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative study. Compared inclusion criteria were (1) preclinical or prodromal AD (amyloid marker abnormal); (2) preclinical or prodromal AD stage-1 (amyloid marker abnormal, injury marker normal); and (3) preclinical or prodromal AD stage-2 (amyloid and injury markers abnormal). Outcome measures were amyloid, neuronal injury, and cognitive markers.

Results

In both subjects with preclinical and prodromal AD stage-2, inclusion criteria resulted in the largest observed decline in brain volumetric measures on magnetic resonance imaging and cognitive markers.

Discussion

Inclusion criteria influence the observed rate of worsening in outcome measures. This has implications for trial design.

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Most cited references 18

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Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI.

Susan Landau, Danielle Harvey, Cindee Madison … (2011)

The Functional Activities Questionnaire (FAQ) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) are frequently used indices of cognitive decline in Alzheimer's disease (AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Finally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline. Copyright © 2009 Elsevier Inc. All rights reserved.

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Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease.

Anne M. Fagan, Chengjie Xiong, Mateusz S. Jasielec … (2014)

Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β1-42 (Aβ1-42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

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Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid.

Michael J Pontecorvo, Ming-Lu Liang, … (2013)

We examined agreement and disagreement between 2 biomarkers of β-amyloid (Aβ) deposition (amyloid positron emission tomography [PET] and cerebrospinal fluid [CSF] Aβ1-42 ) in normal aging and dementia in a large multicenter study. Concurrently acquired florbetapir PET and CSF Aβ were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease participants (n = 374) from the Alzheimer's Disease Neuroimaging Initiative. We also compared Aβ measurements in a separate group with serial CSF measurements over 3.1 ± 0.8 years that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases. Florbetapir and CSF Aβ were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the 2 discordant groups had different profiles: the florbetapir(+) /CSF Aβ(-) group was larger (n = 13) and was made up of only normal and early MCI subjects, whereas the florbetapir(-) /CSF Aβ(+) group was smaller (n = 7) and had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF Aβ trajectories and those actively transitioning from normal to abnormal, but the final CSF Aβ measurements were in good agreement with florbetapir cortical retention. CSF and amyloid PET measurements of Aβ were consistent in the majority of subjects in the cross-sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF Aβ regularly becomes abnormal prior to fibrillar Aβ accumulation early in the course of disease. © 2013 American Neurological Association.

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Author and article information

Contributors

Daniela Bertens

Journal

Journal ID (nlm-ta): Alzheimers Dement (N Y)

Journal ID (iso-abbrev): Alzheimers Dement (N Y)

Title: Alzheimer's & Dementia : Translational Research & Clinical Interventions

Publisher: Elsevier

ISSN (Electronic): 2352-8737

Publication date PMC-release: 21 September 2017

Publication date Collection: November 2017

Publication date (Electronic): 21 September 2017

Volume: 3

Issue: 4

Pages: 513-523

Affiliations

[a ]Alzheimer Centre, Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands

[b ]Alzheimer Research Center, Amsterdam The Netherlands

[c ]Alzheimer Centre, School for Mental Health and Neuroscience (MHeNS), University Medical Centre, Maastricht, The Netherlands

Author notes

[∗ ]Corresponding author. Tel.: +31204448527; Fax: +31204448529. d.bertens@ 123456vumc.nl

[1]

Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database ( adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Article

Publisher ID: S2352-8737(17)30051-3

DOI: 10.1016/j.trci.2017.08.005

PMC ID: 5671625

SO-VID: d28d8515-7e19-4f48-95a4-1018d0982034

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The effect of diagnostic criteria on outcome measures in preclinical and prodromal Alzheimer's disease: Implications for trial design

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Abstract

Introduction

Methods

Results

Discussion

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Alternative approaches to Alzheimer's Disease

Most cited references 18

Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI.

Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease.

Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid.

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