Abstract
BackgroundIn Alzheimer’s disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations.Main bodyAmyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement. Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging (MRI), providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion. Atrophy rates (either hippocampal or whole brain), which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification. Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities (ARIA). Tau PET to measure neurofibrillary tangle burden is currently under development. Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation.ConclusionWe propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI.
Highlights
In Alzheimer’s disease (AD), pathological changes may arise up to 20 years before the onset of dementia
Research criteria from the International Working Group (IWG) [9, 10] and the National Institute on Ageing-Alzheimer Association (NIA-AA) [11,12,13] propose the use of biomarkers to define pre-clinical AD as the disease stage characterised by amyloid pathology, with or without neurofibrillary tangles and/or features of neurodegeneration, even in the absence of clinical manifestations
Due to harmonisation issues in longitudinal and multi-centre settings, we suggest that Resting state functional MRI (rs-fMRI) measures can at present only serve as an exploratory outcome measure in trials. rs-fMRI has already been used as a secondary outcome measure in clinical trials in subjects with AD dementia, and treatment-related effects were found on the default mode network over a 3- to 6-month time period [170, 171]. rs-fMRI is currently being used in multi-centre clinical trials in cognitively normal subjects at increased risk of AD
Summary
Alzheimer’s disease (AD) is the leading cause of dementia worldwide and it is pathologically characterised by the deposition of extracellular β-amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau proteins [1]. Research criteria from the International Working Group (IWG) [9, 10] and the National Institute on Ageing-Alzheimer Association (NIA-AA) [11,12,13] propose the use of biomarkers to define pre-clinical AD as the disease stage characterised by amyloid pathology, with or without neurofibrillary tangles and/or features of neurodegeneration, even in the absence of clinical manifestations. Early-stage biomarkers should predict risk and likely timing of cognitive decline and progression to dementia in a reliable, non-invasive, and cost-effective manner. Trials in non-demented subjects would benefit from biomarkers that can monitor treatment effects and should reflect disease progression, be sensitive to detect pathologically significant changes over time and in response to treatment, and be highly reproducible and reliable in a multi-centre setting. The utility of longitudinal imaging as a run-in for clinical trials, identification of exclusion criteria, and vascular comorbidity were taken into account
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