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Background: Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-β (Aβ) burden. This study aimed to compare SUVR with DVR and to evaluate the effects of underlying Aβ burden and CBF on bias in SUVR in mainly cognitively unimpaired participants. Participants were scanned according to a dual-time window protocol, with either [ 18 F]flutemetamol (N = 90) or [ 18 F]florbetaben (N = 31). The validated basisfunction-based implementation of the two-step simplified reference tissue model was used to derive DVR and R 1 parametric images, and SUVR was calculated from 90 to 110 min post-injection, all with the cerebellar grey matter as reference tissue. First, linear regression and Bland-Altman analyses were used to compare (regional) SUVR with DVR. Then, generalized linear models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R 1 for the global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal region., Results: Despite high correlations (GCA: R 2  ≥ 0.85), large overestimation and proportional bias of SUVR relative to DVR was observed. Negative associations were observed between both SUVR or SUVR bias and R 1, albeit non-significant., Conclusion: The present findings demonstrate that bias in SUVR relative to DVR is strongly related to underlying Aβ burden. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of relative CBF on bias in SUVR appears limited. EudraCT Number: 2018-002277-22, registered on: 25-06-2018., (© 2022. The Author(s).)

Background: The standard reference region (RR) for amyloid-beta (Aβ) PET studies is the cerebellar grey matter (GMCB), while alternative RRs have mostly been utilized without prior validation against the gold standard. This study compared five commonly used RRs to gold standard plasma input-based quantification using the GMCB., Methods: Thirteen subjects from a test-retest (TRT) study and 30 from a longitudinal study were retrospectively included (total: 17 Alzheimer's disease, 13 mild cognitive impairment, 13 controls). Dynamic [ 11 C]PiB PET (90 min) and T1-weighted MR scans were co-registered and time-activity curves were extracted for cortical target regions and the following RRs: GMCB, whole cerebellum (WCB), white matter brainstem/pons (WMBS), whole brainstem (WBS) and eroded subcortical white matter (WMES). A two-tissue reversible plasma input model (2T4k_V b ) with GMCB as RR, reference Logan and the simplified reference tissue model were used to derive distribution volume ratios (DVRs), and standardized uptake value (SUV) ratios were calculated for 40-60 min and 60-90 min intervals. Parameter variability was evaluated using TRT scans, and correlations and agreements with the gold standard (DVR from 2T4k_V b with GMCB RR) were also assessed. Next, longitudinal changes in SUVs (both intervals) were assessed for each RR. Finally, the ability to discriminate between visually Aβ positive and Aβ negative scans was assessed., Results: All RRs yielded stable TRT performance (max 5.1% variability), with WCB consistently showing lower variability. All approaches were able to discriminate between Aβ positive and Aβ negative scans, with highest effect sizes obtained for GMCB (range - 0.9 to - 0.7), followed by WCB (range - 0.8 to - 0.6). Furthermore, all approaches provided good correlations with the gold standard (r ≥ 0.78), while the highest bias (as assessed by the regression slope) was observed using WMES (range slope 0.52-0.67), followed by WBS (range slope 0.58-0.92) and WMBS (range slope 0.62-0.91). Finally, RR SUVs were stable across a period of 2.6 years for all except WBS and WMBS RRs (60-90 min interval)., Conclusions: GMCB and WCB are considered the best RRs for quantifying amyloid burden using [ 11 C]PiB PET.

Background: A 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 [ 18 F]flutemetamol and [ 18 F]florbetaben studies., Methods: Rate constants for subjects across the Alzheimer's disease spectrum (i.e., non-displaceable binding potential (BP ND ) in the range 0.02-0.77 and 0.02-1.04 for [ 18 F]flutemetamol and [ 18 F]florbetaben, respectively) were established based on clinical [ 18 F]flutemetamol (N = 6) and [ 18 F]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 BP ND , outliers (≥ 1.5 × BP ND max) were removed and the bias was assessed using the distribution volume ratio (DVR = BP ND  + 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: [ 18 F]Flutemetamol and [ 18 F]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 [ 18 F]flutemetamol and [ 18 F]florbetaben, respectively)., Conclusions: The length of the interval inversely correlates with the accuracy of the BP ND estimates. Consequently, a dual-time-window protocol of 0-30 and 90-110 min (=maximum of 60 min interval) allows for accurate estimation of BP ND values for both tracers. [ 18 F]flutemetamol: EudraCT 2007-000784-19, registered 8 February 2007, [ 18 F]florbetaben: EudraCT 2006-003882-15, registered 2006.