Cullen, NC;
Zetterberg, H;
Insel, PS;
Olsson, B;
Andreasson, U;
Blennow, K;
Hansson, O;
(2020)
Comparing progression biomarkers in clinical trials of early Alzheimer’s disease.
Annals of Clinical and Translational Neurology
10.1002/acn3.51158.
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Abstract
Objective: To investigate the statistical power of plasma, imaging, and cognition biomarkers as Alzheimer’s disease (AD) clinical trial outcome measures. Methods: Plasma neurofilament light, structural magnetic resonance imaging, and cognition were measured longitudinally in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) in control (amyloid PET or CSF Aβ42 negative [Aβ-] with Clinical Dementia Rating scale [CDR] = 0; n = 330), preclinical AD (Aβ + with CDR = 0; n = 218) and mild AD (Aβ + with CDR = 0.5-1; n = 697) individuals. A statistical power analysis was performed across biomarkers and groups based on longitudinal mixed effects modeling and using several different clinical trial designs. Results: For a 30-month trial of preclinical AD, both the temporal composite and hippocampal volumes were superior to plasma neurofilament light and cognition. For an 18-month trial of mild AD, hippocampal volume was superior to all other biomarkers. Plasma neurofilament light became more effective with increased trial duration or sampling frequency. Imaging biomarkers were characterized by high slope and low within-subject variability, while plasma neurofilament light and cognition were characterized by higher within-subject variability. Interpretation: MRI measures had properties that made them preferable to cognition and pNFL as outcome measures in clinical trials of early AD, regardless of cognitive status. However, pNfL and cognition can still be effective depending on inclusion criteria, sampling frequency, and response to therapy. Future trials will help to understand how sensitive pNfL and MRI are to detect downstream effects on neurodegeneration of drugs targeting amyloid and tau pathology in AD.
| Type: | Article |
|---|---|
| Title: | Comparing progression biomarkers in clinical trials of early Alzheimer’s disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/acn3.51158 |
| Publisher version: | https://doi.org/10.1002/acn3.51158 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10108007 |
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