Abstract
BackgroundUsing surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform.MethodsMEDLINE and Embase (1950–2011) were searched using five search strategies. s were assessed to identify papers meriting review in full. Studies of participants with probable Alzheimer's disease diagnosed by formal criteria were included. We made no restriction on age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate study design to use when developing a disease progression biomarker. We included studies which attempted to draw associations between the changes over time in the biomarker used to investigate disease progression and a clinical measure of disease progression.ResultsFifty-nine studies were finally included. The commonest biomarker modality examined was brain MRI (17/59, 29% of included studies). Median follow-up in included studies was only 1.0 (IQR 0.8–1.7) year and most studies only measured the putative biomarker and clinical measure twice. Included studies were generally of poor quality with small numbers of participants (median 31 (IQR 17 to 64)), applied excessively restrictive study entry criteria, had flawed methodologies and conducted overly simplistic statistical analyses without adjusting for confounding factors.ConclusionsWe found insufficient evidence to recommend the use of any biomarker as an outcome measure for disease progression in Alzheimer's disease trials. However, further investigation into the efficacy of using MRI measurements of ventricular volume and whole brain volume appeared to be merited. A provisional ‘roadmap’ to improve the quality of future disease progression biomarker studies is presented.
Highlights
The rising prevalence of Alzheimer’s disease, the commonest neurodegenerative disorder, and the associated financial and social costs this brings, presents a major challenge to governments of countries with an ageing population [1]
Various clinical trial designs have been developed to try to adjust for symptomatic effects of putative neurodegenerative agents and, allow clinical rating scales to be used as endpoints
Given the methodological and statistical weaknesses we identified in studies of biomarkers for disease progression in Parkinson’s disease (PD) in a previous systematic review [8], we aimed to determine whether the same problems were prevalent in Alzheimer’s disease research
Summary
The rising prevalence of Alzheimer’s disease, the commonest neurodegenerative disorder, and the associated financial and social costs this brings, presents a major challenge to governments of countries with an ageing population [1]. Various clinical trial designs have been developed to try to adjust for symptomatic effects of putative neurodegenerative agents and, allow clinical rating scales to be used as endpoints. These include long-term follow up studies of placebotreated and active-agent treated patients looking for sustained divergence, measuring outcomes following a wash-out period, and delayed start trial designs [2]. The focus of much primary research, is the use of a surrogate outcome biomarker as an endpoint in neuroprotective clinical trials. Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer’s disease exist and how well they perform
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