Amyloid PET imaging: a challenge for research in clinical neuroimaging

Abstract

The development of amyloid targeting PET radioligands is one of the most challenging research and clinical neuroimaging endeavours. The first radiopharmaceutical developed by investigators at the University of Pittsburgh, a derivative of a histopathologic dye (thioflavin-S) used to identify fibrillary Ab-amyloid in microscopic brain tissue sections, was N-methyl-[C]2-(40-methylaminophenyl)-6hydroxybenzothiazole (now termed [C]Pittsburgh Compound-B or [C]PiB) [1]. Shortly following the advent of [C]PiB, several commercial entities began development of radio-fluorinated amyloid probes that would have potential translational clinical uses. At the time of this writing, there are a few probes approved for clinical use by Food and Drug Administration (FDA) and European Medicine Agency (EMA) and several others still in the pipeline. As today, based on the available data, results obtained by PET with amyloid radiopharmaceuticals should not be considered as diagnostic for Alzheimer disease (AD), but rather indicative of the presence of cerebral amyloid deposition. Ab deposition may be found in fact in disorders other than AD, such as dementia with Lewy bodies and amyloid angiopathy. Further researche will solve these issues, possibly increasing the spectrum of applications for amyloid PET imaging. The Society of Nuclear Medicine and Molecular Imaging has recently released Guidelines for the clinical application of amyloid imaging, emphasizing a conservative approach [2]. The SNMMI Guidelines suggest appropriate use of clinical amyloid imaging for distinguishing dementias with a moderate-to-high burden of fibrillary Abamyloid vs. those without amyloid deposition. The specificities of PET findings with the use of the clinically approved tracers have each been confirmed by direct comparisons of PET imaging with subsequent neuropathologic diagnosis at autopsy. Patients with dementia due to Alzheimer disease and some patients with dementia with Lewy bodies are expected to have abnormal (‘‘positive’’) amyloid scans, while patients with other forms of neurodegenerative disorders, such as the frontotemporal dementia spectrum (FTD), Creutzfeld–Jacob disease, and others, to have normal (‘‘negative’’) amyloid scans. Amyloid imaging might be of prognostic value in subjects with mild cognitive impairment (MCI), in whom there is a significant increased risk for progression to AD over 2–3 years following a ‘‘positive’’ amyloid PET scan. On the other hand, amyloid imaging is appropriate neither in patients with typical AD and in asymptomatic elderly subjects, as the imaging results would not lead to changes in diagnostic classification or clinical management, in particular, ‘‘positive’’ amyloid scans may be observed in elderly individuals, that remain asymptomatic for a decade in spite of such finding. It remains possible that some of these individuals may never develop dementia—follow-up research studies are underway at present to evaluate this possibility. Conversely, when patients exhibit deficits and course that are typical of AD, the vast majority will demonstrate ‘‘positive’’ amyloid scans, and the incremental contribution to diagnosis and management will be small. Up to now, the types of patients and clinical circumstances in which amyloid PET imaging could be used are limited to patients with atypical dementia or in clinical K. Frey University of Michigan, Ann Arbor, MI, USA