Abstract
BackgroundA long dynamic scanning protocol may be required to accurately measure longitudinal changes in amyloid load. However, such a protocol results in a lower patient comfort and scanning efficiency compared to static scans. A compromise can be achieved by implementing dual-time-window protocols. This study aimed to optimize these protocols for quantitative [18F]flutemetamol and [18F]florbetaben studies.MethodsRate constants for subjects across the Alzheimer’s disease spectrum (i.e., non-displaceable binding potential (BPND) in the range 0.02–0.77 and 0.02–1.04 for [18F]flutemetamol and [18F]florbetaben, respectively) were established based on clinical [18F]flutemetamol (N = 6) and [18F]florbetaben (N = 20) data, and used to simulate tissue time-activity curves (TACs) of 110 min using a reference tissue and plasma input model. Next, noise was added (N = 50) and data points corresponding to different intervals were removed from the TACs, ranging from 0 (i.e., 90–90 = full-kinetic curve) to 80 (i.e., 10–90) minutes, creating a dual-time-window. Resulting TACs were fitted using the simplified reference tissue method (SRTM) to estimate the BPND, outliers (≥ 1.5 × BPND max) were removed and the bias was assessed using the distribution volume ratio (DVR = BPND + 1). To this end, acceptability curves, which display the fraction of data below a certain bias threshold, were generated and the area under those curves were calculated.Results[18F]Flutemetamol and [18F]florbetaben data demonstrated an increased bias in amyloid estimate for larger intervals and higher noise levels. An acceptable bias (≤ 3.1%) in DVR could be obtained with all except the 10–90 and 20–90-min intervals. Furthermore, a reduced fraction of acceptable data and most outliers were present for these two largest intervals (maximum percentage outliers 48 and 32 for [18F]flutemetamol and [18F]florbetaben, respectively).ConclusionsThe length of the interval inversely correlates with the accuracy of the BPND estimates. Consequently, a dual-time-window protocol of 0–30 and 90–110 min (=maximum of 60 min interval) allows for accurate estimation of BPND values for both tracers.[18F]flutemetamol: EudraCT 2007-000784-19, registered 8 February 2007, [18F]florbetaben: EudraCT 2006-003882-15, registered 2006.
Highlights
A long dynamic scanning protocol may be required to accurately measure longitudinal changes in amyloid load
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 t1/2 = 109.8 min compared to [11C]PiB (Carbon-11 Pittsburgh Compound B) and commercial availability [5, 6]
Amyloid positron emission tomography (PET) allows for quantification of underlying physiological processes, such as the level of Aβ plaque burden [7,8,9,10]
Summary
A long dynamic scanning protocol may be required to accurately measure longitudinal changes in amyloid load. SUVR, 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. Dynamic data acquisition in a dual-time-window protocol ( called “coffee-break” protocol), 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 allow for interleaved scanning protocols, thereby optimizing tracer batch and scanner usage (i.e., costs), while maintaining a high quantitative accuracy
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