LAUSR

With the recent introduction of amyloid PET tracers into clinical use, non-invasive biomarker information on brain amyloidosis is available which challenges the long-accepted gold standard of post mortem histopathology for diagnosing Alzheimer’s disease (AD). Phase 3 amyloid PET studies in end of life patients with post mortem verification of brain amyloid status have arguably shifted the time-point of diagnosing amyloid pathology to ante mortem. Florbetapir, florbetaben, and flutemetamol, the PET tracers utilised for that purpose, share high sensitivity/specificity in detecting/ excluding beta-amyloid aggregates which accumulate in the neocortex of AD brains [1–3]. Further, comparably high discrimination accuracy was reported for these tracers between patients with clinical diagnosis of AD dementia and healthy controls [4, 5]. The main advantages of these tracers are the high image signal associated with these Bhot spot^ imaging tracers and the binary nature of the PET result when applied in certain scenarios (reproducible mild cognitive impairment, early-onset AD dementia, Bpossible^ AD dementia according to clinical testing [6, 7]). This is because, in line with the amyloid cascade theory of AD [8], amyloid pathology should be full-blown by the time cognitive decline manifests. This favourable scenario motivated the regulatory authorities to approve these tracers based solely on a visual PET assessment by readers who have passed a tracer-specific training. Respective training programs utilised for that purpose describe a series of rules referent to the question of whether there is grey vs. white matter contrast. In parallel to these efforts to establish read algorithms, in the USA the IDEAS study [9] is underway, aimed at providing outcome data about the clinical relevance of amyloid PETcrucial for future reimbursement. In Europe, this effort will soon be followed by the AMYPAD study [10]. Besides the use of amyloid PET for primary diagnosis of brain amyloid pathology in conjunction with AD, the above tracers are intensively utilized in drug testing trials [11] for confirming eligibility and monitoring the impact of therapy on brain amyloidosis. Yet, like any diagnostic test, PET amyloid visual assessments are not perfect and technical and biological factors pose challenges to accurate scan interpretation, particularly for the inexperienced reader. Further, some concerns have been raised in the past on the validity of visual read rules [12] which might result in relevant inter-reader variability [13]. One principle advantage of the PET imaging technique lies in its quantitative nature. The question of how important quantitative data are in cases of amyloid PET image analysis depends on the question to be addressed by the PET procedure. There is no doubt that in cases where amyloid imaging is used for follow-up evaluation/therapy monitoring quantitation is important. In this instance quantitative methods using dynamic imaging and kinetic modelling should ideally be performed. However, up to now, the logistical practicalities involved in large multi-centre trials favour the simpler semiquantitative, albeit biased standardized uptake value ratio (SUVr) approach. Further, with the prospect of effective and safe amyloid aggregate-cleaving drugs comes the requirement of early and accurate identification of pathologic brain amyloid, including in subjects at high risk, but prior to cognitive symptoms. In such scenarios where there might be less pronounced amyloid load, quantitative measures might prove more This Editorial Commentary refers to the article http://dx.doi.org/10.1007/ s00259-016-3601-4.