Optimized dual-time-window protocols for quantitative [¹⁸F]flutemetamol and [¹⁸F]florbetaben PET studies

Deposition of amyloid-beta (Aβ) plaques in the brain is the earliest in vivo measurable hallmark in the development of Alzheimer’s disease (AD), which is the most common type of dementia [1‐3]. Therefore, visualization of Aβ deposits in vivo is essential for improving early diagnosis and monitoring treatment effects [4]. To this end, various positron emission tomography (PET) amyloid tracers have been developed [5]. Among those, fluorine-18 (18F)-labeled tracers approved by the European Medicines Agency (EMA)/Food and Drug Administration (FDA) are of special interest for clinical trials due to their relatively long half-life t_1/2 = 109.8 min compared to [¹¹C]PiB (Carbon-11 Pittsburgh Compound B) and commercial availability [5, 6].

In addition to visualization, amyloid PET allows for quantification of underlying physiological processes, such as the level of Aβ plaque burden [7‐10]. For diagnostic purposes, a static scan acquired at pseudo-equilibrium, using a tracer-specific approved method, has been deemed sufficient in combination with visual assessment of the images. In research settings, this simplified protocol is commonly used to calculate the standardized uptake value ratio (SUVR) [5]. SUVR, however, is only a semi-quantitative parameter that is known to be affected by both scanning time window and (changes in) blood flow [11, 12]. Given this dependency, full quantification using pharmacokinetic modeling may be required to obtain higher overall sensitivity for measuring longitudinal changes (e.g., for monitoring disease progression or treatment response), especially during the early stages of the disease when amyloid is still accumulating. Pharmacokinetic modeling, however, requires a dynamic scanning protocol, which can last for up to 2 h depending on the actual tracer. These long acquisition protocols result in lower patient comfort and lesser efficient use of both scanner and tracer batch, in addition to an increased risk of motion artifacts. Dynamic data acquisition in a dual-time-window protocol (also called “coffee-break” protocol), however, can be used to reduce overall scanning time, in which data are acquired separately for early and late phases. Such a protocol provides a resting period for the patient and, when long enough, may also allow for interleaved scanning protocols, thereby optimizing tracer batch and scanner usage (i.e., costs), while maintaining a high quantitative accuracy.

So far, some studies have used a dual-time-window protocol using static acquisition of amyloid-PET data. An early scan (i.e., 0–10 min p.i.) was proposed in addition to the (standard) late static scan, as it has been reported that the early scan may provide information on metabolism and neuronal injury, possibly circumventing the need for additional [¹⁸F]FDG imaging [12‐16]. Recently, Bullich and colleagues demonstrated that the non-displaceable binding potential (BP_ND) obtained using a dual-time-window acquisition protocol (0–30 and 120–140 min p.i.) correlated well with BP_ND obtained using a full dynamic acquisition protocol of 140 min [17]. This [¹⁸F]florbetaben study, however, did not report details about different resting periods, nor did it assess the robustness of the dual-time-window protocol for subjects across the AD spectrum and for different noise levels (e.g., for regions of different sizes).

The purpose of the present simulation study was to define optimal dual-time-window acquisition protocols for [¹⁸F]florbetaben and [¹⁸F]flutemetamol, both in terms of patient comfort and throughput, while maintaining high quantitative accuracy. These simulations were focused on early stages of the disease, given the potential value of amyloid imaging to guide interventions aimed at secondary prevention of AD dementia.

The present pharmacokinetic simulation study demonstrated that, for [¹⁸F]flutemetamol and [¹⁸F]florbetaben, the introduction of a break with a maximum of 60 min in a dual-time-window acquisition protocol (early interval of 0–30 min followed by a late interval of 90–110 min) results in a minimal loss in quantitative accuracy while presenting major logistic advantages as compared with full dynamic acquisitions. Therefore, this protocol could serve as suitable alternative in research or clinical trial settings where accurate and fully quantitative measurements might be required.

Analysis of the 2T4k_V_b noiseless full TACs showed a systematic bias (0.17–1.95% for [¹⁸F]flutemetamol and 2.62–6.04% for [¹⁸F]florbetaben) in SRTM-derived DVR values compared with simulated DVR values. These findings are in line with previous studies reporting that kinetics of [¹⁸F]flutemetamol and [¹⁸F]florbetaben are better described by a two-tissue compartment model in target as well as reference tissues [8, 18]. In addition, Nelissen et al. showed that there were similar levels of binding in the second reference tissue compartment for both healthy control and AD subjects and therefore concluded that this binding is likely due to (relatively slow) non-specific retention [18]. As this violates one of the assumptions of SRTM, a slight bias in DVR estimates can be expected [19, 30]. Given the aim of validating a dual-time-window protocol for a reference tissue-based approach, TACs were both generated and fitted according to the SRTM model to prevent a systematic bias in the results.

A first examination of SRTM-derived \( {\mathrm{BP}}_{\mathrm{ND}}^{\mathrm{fit}} \) values revealed that most outliers were observed for fits of the 10–90-min interval, and, to a lesser extent, also for fits of the 20–90-min interval. In addition, compared with the full-kinetic curve, the bias in DVR only exceeded previously reported [¹¹C]PIB TRT values, of which [¹⁸F]flutemetamol is an analog, for the 10–90 and 20–90-min intervals for [¹⁸F]flutemetamol [9, 10]. For the other dual-time-window protocols, the bias remained ≤ 3.1%. Analysis of [¹⁸F]florbetaben data showed a bias of ≤ 9.1% for the 10–90-min interval and ≤ 5.0% for the 20–90 interval for the highest noise levels, while for all intervals it was ≤ 1.9%. The latter well within previously reported TRT values for [¹⁸F]florbetaben SUVR data (ranging between 2.9% HC and 6.2% AD) [31]. Reported AUC values also showed a general trend of worse values for longer breaks and higher noise level, with the exception of some extremely low BP_ND cases, where the performance of SRTM is known to be suboptimal [10].

Finally, the bias plots of SRTM-generated TACs demonstrated that bias in SRTM-derived R₁ increased as a function of noise and interval for both tracers. More specifically, a larger error in R₁ (> 3% for [¹⁸F]flutemetamol and > 1% for [¹⁸F]florbetaben) was observed for the 10–90-min intervals compared with the other intervals. For practical applications, this error would be negligible since the TRT of flow is known to be approximately 9% [32]. As expected, the results showed that the length of the interval is related to bias in \( {\mathrm{BP}}_{\mathrm{ND}}^{\mathrm{fit}} \) or DVR and the number of outliers. More specifically, results suggest that it is not advisable to use the 10–90 and 20–90-min intervals for full quantification, especially due to the relatively large percentage of outliers and larger bias in DVR compared with other intervals. Moreover, the observed larger amount of unusable data would result in smaller power to detect changes in clinical trials.

Shorter scan durations are better for the patient and, as such, longer breaks would be preferred. Since the 10–90 and 20–90-min intervals result in a large number of outliers and larger bias, the 30–90-min interval would be a good compromise. This interval would have the additional advantage of a 60-min break, which may allow for interleaved scanning protocols. Consequently, the 30–90-min interval is recommended as the optimal trade-off between patient comfort and quantitative accuracy (bias in DVR < 2% and a maximum of 18% outliers for highest noise level and \( {\mathrm{BP}}_{\mathrm{ND}}^{\mathrm{fit}} \)). This conclusion is in agreement with recent work of Bullich et al. regarding the optimal [¹⁸F]florbetaben dual-time-window protocol [17]. Based on their analysis of clinical data, which did not include the 90–110-min diagnostic window, a dual-time-window protocol of 0–30 and 120–140 min was described as optimal. However, their simulations also supported that 0–30 and 90–110-min scanning times would maintain the best compromise between quantitative accuracy and patient comfort. The present simulation study, including TACs representing the AD spectrum and different noise levels, further validated their findings.

A major advantage of a 60-min gap in the scanning protocol is that it allows for interleaved scanning protocols, in which the first scan of the second patient can be acquired within the resting period (interval) of the first patient. An interleaved scanning protocol would increase both patient throughput and efficient use of tracer batches, thereby decreasing costs. An assessment of the practical feasibility of such an interleaved scanning protocol is beyond the scope of the present study and needs to be addressed in future studies. Main limitations of the current study include the use of fixed K₁ and k₂ parameters for simulations, the limited sample size of the available clinical dataset, and the extrapolation of TRT variability from other radiotracers to this work. The first limits the possibility of assessing the impact of changes in cerebral blood flow on dual-time-window protocol-based quantification, but it can be expected to introduce only small additional bias over and above the one introduced by the protocol itself [11]. Regarding the second, additional clinical data would have allowed the verification of the simulation results, which remains a goal for future work once larger cohorts are available. With respect to extrapolating TRT variability, although values from other tracers might not directly translate to our data, they are expected to be in comparable ranges [24]. In addition, although outside of the scope of this study, the evaluation of parametric methods for quantification of dual-time-window-derived data is warranted, which would require imaging data in order to optimize image contrast and reduce noise and artifacts. Finally, it must be noted that the goal of this study was not to compare these two tracers, but to identify the optimal dynamic dual-time-window scanning protocol for both of them. In order to make a head-to-head comparison between tracers, PET imaging data from both tracers within the same patient would be required.

Accurate estimates of \( {\mathrm{BP}}_{\mathrm{ND}}^{\mathrm{fit}} \) can be obtained for both [¹⁸F]flutemetamol and [¹⁸F]florbetaben using a 60-min dual-time-window protocol, with dynamic scanning from 0 to 30 and again from 90 to 110 min. This protocol results in a limited number of outliers, and an acceptable bias in \( {\mathrm{BP}}_{\mathrm{ND}}^{\mathrm{fit}} \) and DVR estimates. Moreover, it enables interleaved scanning protocols, optimizing tracer batch usage and patient throughput, thereby reducing costs and improving patient comfort.