Assessment of 18F-Florbetaben Whole-body PET for the Detection of Cardiac and Extracardiac Sites of Amyloid Deposits

Overview

Although being classified as a rare disease, cardiac amyloidosis constitutes an increasing cause of heart failure, which is often overlooked and thus poorly managed. Amyloidosis involves deposits of light chain immunoglobulins in the immunoglobulin light chain amyloidosis (AL) type, but it may also be of a hereditary type in mutated transthyretin amyloidosis (ATTRm) or of a senile type in wildtype transthyretin forms (ATTRwt). Myocardial biopsy remains a gold standard for definitive diagnosis but it is a traumatic technique which only provides information on a limited number of sampled sites. Useful but not fully specific signs of cardiac amyloidosis may also be provided by Magnetic Resonance Imaging or MRI (delayed retention imaging) and echocardiography (longitudinal strain pattern). Notwithstanding the above, relatively specific markers of amyloid plaques are now available in Positron Emission Tomography (PET). These markers are primarily fluorinated tracers which have been developed for the diagnosis of Alzheimer's disease. Two of these have already been the subject of feasibility studies in the setting of cardiac amyloidosis diagnosis, on a maximum of 10 amyloidosis patients but with very favorable results. The hypothesis is that one of these two tracers, Florbetaben labelled with Fluorine-18-Florbetaben (18F-Florbetaben) used in the study, has sufficiently strong and prolonged binding kinetics at the level of the amyloid plaques to allow: (i) achieving whole-body PET recordings and thus, (ii) identifying not only cardiac amyloidosis but also extracardiac binding sites, particularly those readily accessible to biopsy sampling. This hypothesis has been strengthened by a recent case report illustrating the ability of whole-body florbetaben-PET to image not only cardiac but also extra-cardiac sites of amyloid deposits (Clin Nucl Med. 2017;42(1):50-3).

In addition, distinctive imaging patterns pointing to amyloidosis may also be documented by other imaging techniques although insufficiently specific (e.g. decreased cardiac uptake of metaiodobenzylguanidine (MIBG), evocative pattern of delayed retention at Magnetic Resonance Imaging (MRI) or at strain echocardiography. Specific markers of amyloid plaques have been developed for the diagnosis of Alzheimer's disease and were initially labeled with carbon-11 and more recently, with fluor-18. Most of these markers have already been the subject of feasibility studies on limited numbers of amyloidosis patients (max 10) but with favorable results. In a previous pilot study, one of these tracers, the 18F-Florbetaben used in the present study-protocol, exhibited particularly slow kinetics, with differences in cardiac uptake between patients and controls still being documented as late as 80-min following injection. This uptake was also found to be somewhat lower in the 5 ATTR patients comparatively to the 5 AL patients. It may be hypothesized that 18F-Florbetaben has sufficiently slow and prolonged binding kinetics at the level of the amyloid plaques to allow: (i) achieving whole-body PET recordings with current recording times of 20 to 30 min and thus, (ii) identifying not only cardiac amyloidosis but also extracardiac binding sites, particularly those readily accessible to biopsy sampling. This hypothesis has just been strengthened by a recent case report, published by investigators involved in the present project and illustrating the ability of whole-body 18F-Florbetaben-PET to image not only cardiac but also various extracardiac sites of amyloid deposits.The proposed study would be the first in which the sample size would be sufficient to provide a credible assessment of the ability of PET, using an amyloid plaque tracer, to identify cardiac amyloidosis and with a possible separate analysis of ATTR and AL forms. Moreover, it would also constitute the first study involving an extensive use of whole-body PET imaging to assess the benefit of amyloidosis detection, not only at the cardiac level, but also at peripheral sites, especially those accessible for biopsy (tongue, rectum, salivary glands, carpal tunnel, liver, subcutaneous tissue, thyroid,...). Being able to confirm or invalidate the diagnosis of cardiac amyloidosis in a non-invasive manner and by guiding biopsy sampling to the most active extracardiac sites would be a major step forward for these patients whose diagnosis is most often established too late, i.e. at an advanced stage of heart failure. In the longer term,18F-Florbetaben whole-body PET could be helpful for the non-invasive monitoring of the evolution of cardiac as well as extracardiac sites of amyloid deposits under dedicated specific treatments (chemotherapies in AL forms and specific treatments currently under investigation for the AL forms). Such monitoring is still impossible today.