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Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).

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Kinetic modeling is at the basis of most quantification methods for dynamic PET data. Specific software is required for it, and a free and easy-to-use kinetic analysis toolbox can facilitate routine work for clinical research. The relevance of kinetic modeling for neuroimaging encourages its incorporation into image processing pipelines like those of SPM, also providing preprocessing flexibility to match the needs of users. The aim of this work was to develop such a toolbox: QModeling. It implements four widely-used reference-region models: Simplified Reference Tissue Model (SRTM), Simplified Reference Tissue Model 2 (SRTM2), Patlak Reference and Logan Reference. A preliminary validation was also performed: The obtained parameters were compared with the gold standard provided by PMOD, the most commonly-used software in this field. Execution speed was also compared, for time-activity curve (TAC) estimation, model fitting and image generation. QModeling has a simple interface, which guides the user through the analysis: Loading data, obtaining TACs, preprocessing the model for pre-evaluation, generating parametric images and visualizing them. Relative differences between QModeling and PMOD in the parameter values are almost always below 10. The SRTM2 algorithm yields relative differences from 10 to 10 when [Formula: see text] is not fixed, since different, validated methods are used to fit this parameter. The new toolbox works efficiently, with execution times of the same order as those of PMOD. Therefore, QModeling allows applying reference-region models with reliable results in efficient computation times. It is free, flexible, multiplatform, easy-to-use and open-source, and it can be easily expanded with new models.