Kinetics and 28-day test-retest repeatability and reproducibility of [11C]UCB-J PET brain imaging.

[11C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [11C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [11C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K1) and volume of distribution (VT) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_VB and 2T4k_VB described the [11C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for VT, DVR and SRTM BPND were -2.2% ± 8.5, 0.4% ± 12.0 and -8.0% ± 10.2, averaged over all subjects. [11C]UCB-J kinetics can be well described by a 1T2k_VB model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for VT, DVR and BPND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [11C]UCB-J PET.

Repeatability of parametric methods for [18F]florbetapir imaging in Alzheimer's disease and healthy controls: A test-retest study.

Accumulation of amyloid beta (Aß) is one of the pathological hallmarks of Alzheimer's disease (AD), which can be visualized using [18F]florbetapir positron emission tomography (PET). The aim of this study was to evaluate various parametric methods and to assess their test-retest (TRT) reliability. Two 90 min dynamic [18F]florbetapir PET scans, including arterial sampling, were acquired (n = 8 AD patient, n = 8 controls). The following parametric methods were used; (reference:cerebellum); Logan and spectral analysis (SA), receptor parametric mapping (RPM), simplified reference tissue model2 (SRTM2), reference Logan (rLogan) and standardized uptake value ratios (SUVr(50-70)). BPND+1, DVR, VT and SUVr were compared with corresponding estimates (VT or DVR) from the plasma input reversible two tissue compartmental (2T4k_VB) model with corresponding TRT values for 90-scan duration. RPM (r2 = 0.92; slope = 0.91), Logan (r2 = 0.95; slope = 0.84) and rLogan (r2 = 0.94; slope = 0.88), and SRTM2 (r2 = 0.91; slope = 0.83), SA (r2 = 0.91; slope = 0.88), SUVr (r2 = 0.84; slope = 1.16) correlated well with their 2T4k_VB counterparts. RPM (controls: 1%, AD: 3%), rLogan (controls: 1%, AD: 3%) and SUVr(50-70) (controls: 3%, AD: 8%) showed an excellent TRT reliability. In conclusion, most parametric methods showed excellent performance for [18F]florbetapir, but RPM and rLogan seem the methods of choice, combining the highest accuracy and best TRT reliability.

Hippocampal [18F]flortaucipir BPND corrected for possible spill-in of the choroid plexus retains strong clinico-pathological relationships.

BACKGROUND: Off-target [18F]flortaucipir (tau) PET binding in the choroid plexus causes spill-in into the nearby hippocampus, which may influence the correlation between [18F]flortaucipir binding and measures of cognition. Previously, we showed that partial volume correction (combination of Van Cittert iterative deconvolution and HYPR denoising; PVC HDH) and manually eroding the hippocampus resulted in a significant decrease of the choroid plexus spill-in. In this study, we compared three different approaches for the quantification of hippocampal [18F]flortaucipir signal using a semi-automated technique, and assessed correlations with cognitive performance across methods. METHODS: Dynamic 130 min [18F]flortaucipir PET scans were performed in 109 subjects (45 cognitively normal subjects (CN) and 64 mild cognitive impairment/Alzheimer's disease (AD) dementia patients. We extracted hippocampal binding potential (BPND) using receptor parametric mapping with cerebellar grey matter as reference region. PVC HDH was performed. Based on our previous study in which we manually eroded 40% ± 10% of voxels of the hippocampus, three hippocampal volumes-of-interest (VOIs) were generated: a non-optimized 100% hippocampal VOI [100%], and combining HDH with eroding a percentage of the highest hippocampus BPND voxels (i.e. lowering spill-in) resulting in optimized 50%[50%HDH] and 40%[40%HDH] hippocampal VOIs. Cognitive performance was assessed with the Mini-Mental State Examination (MMSE) and Rey auditory verbal learning delayed recall. We performed receiver operating characteristic analyses to investigate which method could best discriminate MCI/AD from controls. Subsequently, we performed linear regressions to investigate associations between the hippocampal [18F]flortaucipir BPND VOIs and MMSE/delayed recall adjusted for age, sex and education. RESULTS: We found higher hippocampal [18F]flortaucipir BPND in MCI/AD patients (BPND100%=0.27±0.15) compared to CN (BPND100%= 0.07±0.13) and all methods showed comparable discriminative effects (AUC100%=0.85[CI=0.78-0.93]; AUC50%HDH=0.84[CI=0.74-0.92]; AUC40%HDH=0.83[CI=0.74-0.92]). Across groups, higher [18F]flortaucipir BPND was related to lower scores on MMSE (standardized ß100%=-0.38[CI=-0.57-0.20]; ß50%HDH= -0.37[CI=-0.54-0.19]; ß40%HDH=-0.35[CI=-0.53-0.17], all p<0.001) and delayed recall (standardized ß100%=-0.64[CI=-0.79-0.49]; ß50%HDH= -0.61[CI=-0.76-0.46]; ß40%HDH=-0.59[CI=-0.75-0.44]; all p<0.001), with comparable effect sizes for all hippocampal VOIs. CONCLUSIONS: Hippocampal tau load measured with [18F]flortaucipir PET is strongly associated with cognitive function. Both discrimination between diagnostic groups and associations between hippocampal [18F]flortaucipir BPND and memory were comparable for all methods. The non-optimized 100% hippocampal VOI may be sufficient for clinical interpretation. However, proper correction for choroid plexus spillover and may be required in case of smaller effect sizes between subject groups or for longitudinal studies.

Test-retest repeatability of [18F]Flortaucipir PET in Alzheimer's disease and cognitively normal individuals.

The aim of this study was to investigate the test-retest (TRT) repeatability of various parametric quantification methods for [18F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer's disease and six cognitively normal subjects. All underwent two 130-min dynamic [18F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40-60, 80-100 and 110-130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest-test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68-2.15) to 6.84% (2.99-11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78-3.58) vs. SUVr80-100: 3.05% (1.28-5.52), p < 0.001. Furthermore, for SUVr80-100 and SUVr110-130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.

Quantification of [18F]florbetapir: A test-retest tracer kinetic modelling study.

Accumulation of amyloid beta can be visualized using [18F]florbetapir positron emission tomography. The aim of this study was to identify the optimal model for quantifying [18F]florbetapir uptake and to assess test-retest reliability of corresponding outcome measures. Eight Alzheimer's disease patients (age: 67 ± 6 years, Mini-Mental State Examination (MMSE): 23 ± 3) and eight controls (age: 63 ± 4 years, MMSE: 30 ± 0) were included. Ninety-minute dynamic positron emission tomography scans, together with arterial blood sampling, were acquired immediately following a bolus injection of 294 ± 32 MBq [18F]florbetapir. Several plasma input models and the simplified reference tissue model (SRTM) were evaluated. The Akaike information criterion was used to identify the preferred kinetic model. Compared to controls, Alzheimer's disease patients had lower MMSE scores and evidence for cortical Aß pathology. A reversible two-tissue compartment model with fitted blood volume fraction (2T4k_VB) was the preferred model for describing [18F]florbetapir kinetics. SRTM-derived non-displaceable binding potential (BPND) correlated well (r2 = 0.83, slope = 0.86) with plasma input-derived distribution volume ratio. Test-retest reliability for plasma input-derived distribution volume ratio, SRTM-derived BPND and SUVr(50-70) were r = 0.88, r = 0.91 and r = 0.86, respectively. In vivo kinetics of [18F]florbetapir could best be described by a reversible two-tissue compartmental model and [18F]florbetapir BPND can be reliably estimated using an SRTM.