1. 
 Salvado, G., et al.
(författare)

Centiloid cutoff values for optimal agreement between PET and CSF core AD biomarkers
 2019

Ingår i: Alzheimers Research & Therapy.  17589193. ; 11

Tidskriftsartikel (refereegranskat)abstract
 BackgroundThe Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cutoff values of this continuous measurement enable the consistent operationalization of decisionmaking for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.MethodsA total of 516 participants of the ALFA+ Study (N=205) and ADNI (N=311) underwent amyloid PET imaging ([F18]flutemetamol and [F18]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys (R) tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cutoffs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of A(42), tTau, pTau, and their ratios, using preestablished reference cutoff values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cutoffs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.ResultsAll Centiloid cutoffs fell within the range of 2535, except for CSF A(42) that rendered an optimal cutoff value of 12 CL. As expected, the agreement of tau/A(42) ratios was higher than that of CSF A(42). Centiloid cutoff robustness was confirmed even when established in an independent cohort and against variations of CSF cutoffs.ConclusionsA cutoff of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cutoffs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.Trial registrationALFA+ Study, NCT02485730ALFA PET Substudy, NCT02685969


2. 
 Heeman, F., et al.
(författare)

Optimized dualtimewindow protocols for quantitative F18 flutemetamol and F18 florbetaben PET studies
 2019

Ingår i: Ejnmmi Research.  2191219X. ; 9

Tidskriftsartikel (refereegranskat)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 dualtimewindow protocols. This study aimed to optimize these protocols for quantitative [F18]flutemetamol and [F18]florbetaben studies.MethodsRate constants for subjects across the Alzheimer's disease spectrum (i.e., nondisplaceable binding potential (BPND) in the range 0.020.77 and 0.021.04 for [F18]flutemetamol and [F18]florbetaben, respectively) were established based on clinical [F18]flutemetamol (N=6) and [F18]florbetaben (N=20) data, and used to simulate tissue timeactivity curves (TACs) of 110min 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., 9090=fullkinetic curve) to 80 (i.e., 1090) minutes, creating a dualtimewindow. Resulting TACs were fitted using the simplified reference tissue method (SRTM) to estimate the BPND, outliers (1.5xBP(ND) 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[F18]Flutemetamol and [F18]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 1090 and 2090min 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 [F18]flutemetamol and [F18]florbetaben, respectively).ConclusionsThe length of the interval inversely correlates with the accuracy of the BPND estimates. Consequently, a dualtimewindow protocol of 030 and 90110min (=maximum of 60min interval) allows for accurate estimation of BPND values for both tracers.[F18]flutemetamol: EudraCT 200700078419, registered 8 February 2007, [F18]florbetaben: EudraCT 200600388215, registered 2006.

