First-in-human evaluation of 6-bromo-7-[11C]methylpurine, a PET tracer for assessing the function of multidrug resistance-associated proteins in different tissues.

PURPOSE: Multidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer's and chronic respiratory disease. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to measure MRP1 function in rodents. In this study, [11C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues. METHODS: Thirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (kE, h- 1) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology. RESULTS: Mean kE and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h- 1 (- 4 ± 24%), cerebellum: 0.033 ± 0.009 h- 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h- 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h- 1 (30 ± 38%), lungs: 0.875 ± 0.095 h- 1 (- 3 ± 11%), myocardium: 0.641 ± 0.105 h- 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h- 1 (14 ± 16%), and liver: 0.685 ± 0.072 h- 1 (7 ± 9%). Significant sex differences were found for kE in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women. CONCLUSION: LAFOV PET/CT with [11C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of kE in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [11C]BMP was in the typical range of 11C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans. TRIAL REGISTRATION: EudraCT 2021-006348-29. Registered 15 December 2021.

Test-retest variability of plasma biomarkers in Alzheimer's disease and its effects on clinical prediction models.

INTRODUCTION: The effect of random error on the performance of blood-based biomarkers for Alzheimer's disease (AD) must be determined before clinical implementation. METHODS: We measured test-retest variability of plasma amyloid beta (Aß)42/Aß40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) Aß status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms. RESULTS: Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (Aß42/Aß40) to 25% (GFAP). This variability reduced the performance of the biomarkers (≈ΔAUC [area under the curve] -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%). DISCUSSION: Clinical prediction models combining plasma biomarkers-particularly p-tau217-exhibit high performance and are less effected by random error. Individuals with unstable predicted outcomes ("gray zone") should be recommended for further tests.

Test-retest variability for quantitative two-dimensional and Doppler measurements in the fetus.

OBJECTIVES: Echocardiography is used to quantitatively characterize cardiovascular function in fetuses with cardiac abnormalities and inform decisions for fetal or perinatal interventions. It is clinically important to understand the reproducibility of these measures, particularly between testers. While studies have reported intra-observer variability and inter-observer variability, little is known about test-retest variability for these measures. We hypothesized that even in a high volume echocardiography laboratory, quantitative measurements will demonstrate higher test-retest variability compared with inter-observer variability and intra-observer variability of the same measurements. METHODS: Prospective study of uncomplicated, singleton pregnancies to evaluate fetal measures of cardiovascular function obtained by echocardiography. One sonographer obtained predefined variables, and then, a second sonographer obtained the same variables 15 minutes after the first sonographer. Separate data acquisitions were obtained by the two sonographers to evaluate test-retest variability. Intra-observer variability and inter-observer variability were also evaluated. RESULTS: Thirty fetuses between 17- and 36-week gestation were enrolled. Time-based variables had the best intra-observer agreement and inter-observer agreement (1.2%-7.4%), while 2D (7.5%-10%), M-mode (4.9%-10.1%), and velocity-time integral (VTI; 2.6%-13.8%) measurements had poorer agreement. For all variables, test-retest agreement was worse (3%-32.1%), particularly for measurement of myocardial performance index (MPI; 19.7%-21.1%), cardiac output estimation (27.2%-27.9%), and VTI-based indices (14.7%-32.1%). CONCLUSIONS: In a laboratory highly experienced in quantitative fetal echocardiography, intra-observer agreement and inter-observer agreement are good for most quantitative parameters. However, test-retest agreement is fair or poor for several variables, notably the MPI, cardiac output estimation, and VTI-based indices. Understanding how these measures vary between separate acquisitions is important for clinical interpretation and decision making.

Going wireless and booth-less for hearing testing in industry.

OBJECTIVE: To assess the test-retest variability of hearing thresholds obtained with an innovative, mobile wireless automated hearing-test system (WAHTS) with enhanced sound attenuation to test industrial workers at a worksite as compared to standardised automated hearing thresholds obtained in a mobile trailer sound booth. DESIGN: A within-subject repeated-measures design was used to compare air-conducted threshold tests (500-8000 Hz) measured with the WAHTS in six workplace locations, and a third test using computer-controlled audiometry obtained in a mobile trailer sound booth. Ambient noise levels were measured in all test environments. STUDY SAMPLE: Twenty workers served as listeners and 20 workers served as operators. RESULTS: On average, the WAHTS resulted in equivalent thresholds as the mobile trailer audiometry at 1000, 2000, 3000 and 8000 Hz and thresholds were within ±5 dB at 500, 4000 and 6000 Hz. CONCLUSIONS: Comparable performance may be obtained with the WAHTS in occupational audiometry and valid thresholds may be obtained in diverse test locations without the use of sound-attenuating enclosures.

Nasalance Variability in 3- to 5-Year-Old Children during Production of Speech Stimulus in Three Vowel Contexts.

OBJECTIVE: The purpose of this study was to determine whether age and vowel contexts influence test-retest nasalance score variability in typically developing Korean children. PARTICIPANTS: Forty-five 3- to 5-year-old children with normal speech and resonance participated in the study. METHODS: All subjects were asked to repeat three 4-syllable speech stimuli in high, low, or mixed vowel contexts twice after the examiner. An immediate test-retest nasalance score was assessed with no headgear change. Test and retest variability in nasalance scores was examined based on the absolute difference in nasalance scores of the first and second repetition for each stimulus. RESULTS: A significant main effect of the vowel context on variability in nasalance scores was found, but the effect of age on nasalance variability was not significant. Mean absolute difference in nasalance scores for the stimuli in the high vowel contexts was significantly greater than for the stimuli in the low and mixed vowel contexts. CONCLUSIONS: The results suggested that variability in nasalance scores might not decrease with age and tend to show considerable individual variations. Increased variability in nasalance scores in the high vowel context might be associated with aerodynamic and acoustic characteristics resulting from physiological aspects of the vowel /i/.

Serotonin 2A receptor agonist binding in the human brain with [(11)C]Cimbi-36: Test-retest reproducibility and head-to-head comparison with the antagonist [(18)F]altanserin.

INTRODUCTION: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C]Cimbi-36 and the 5-HT2A receptor antagonist [(18)F]altanserin. METHODS: Sixteen healthy volunteers (mean age 23.9 ± 6.4years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [(11)C]Cimbi-36; eight were scanned twice to determine test-retest variability in [(11)C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [(18)F]altanserin. Regional differences in the brain distribution of [(11)C]Cimbi-36 and [(18)F]altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. RESULTS: Test-retest variability of [(11)C]Cimbi-36 non-displaceable binding potential (BPND) was consistently <5% in high-binding regions and lower for reference tissue models as compared to a 2-tissue compartment model. We found a highly significant correlation between regional BPNDs measured with [(11)C]Cimbi-36 and [(18)F]altanserin (mean Pearson's r: 0.95 ± 0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [(11)C]Cimbi-36 as compared to [(18)F]altanserin was found in the choroid plexus and hippocampus in the human brain. CONCLUSIONS: Excellent test-retest reproducibility highlights the potential of [(11)C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [(11)C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors.

Reproducibility in the global indices for multifocal visual evoked potentials and Humphrey visual fields in controls and glaucomatous eyes within a 2-year period.

PURPOSE: In previous studies, we applied receiver operating characteristic curve analysis to the signal-to-noise ratio distributions in the signal and noise windows of multifocal VEP (mfVEP) response. The areas under the curve thus obtained (SNR-AUC) were found to quantitatively detect glaucomatous visual field damage. The present study evaluated the reproducibility of SNR-AUC and the Humphrey visual field (HVF) global indices in 37 eyes with primary open angle glaucoma (POAG; POAG group) and in 30 controls (control group) within a 2-year period. METHODS: The HVF SITA standard 24-2 and mfVEP were recorded at three separate sessions for each individual. The intersession variability for SNR-AUC, mean deviation (MD), and pattern standard deviation (PSD) was evaluated using the repeated measures of analysis of variance and Bland-Altman plots. The logarithmically converted coefficients of variation (CV) of PSD and SNR-AUC were compared between the control and POAG groups. Linear regression analyses were performed on the logarithmic CV of SNR-AUC against the average MD, PSD, and SNR-AUC. RESULTS: SNR-AUC in the POAG group was significantly lower and its CV was greater compared with the control group (P < 0.0001). MD value recorded at the third visit had significantly improved than that at the first visit in the control group (analysis of variance, P = 0.03), whereas PSD value was significantly worse in the POAG group (P = 0.024). In the POAG group, SNR-AUC CV increased as the glaucoma stage became more advanced when evaluated by any functional parameters tested (i.e., MD, PSD, or SNR-AUC). CONCLUSIONS: The SNR-AUC of mfVEP showed a high reproducibility in control group, whereas it fluctuated more in the POAG group according to the disease severity. MD in the control group and PSD in POAG group fluctuated among sessions during the 2-year period.

Test retest variability in stereoacuity measurements.

Background: A clinician's choice of stereotest is influenced by the robustness of the measurement, in terms of sensitivity, specificity and test-retest variability. In relation to the latter aspect, there are limited data on the test-retest variability of these new tests and how they compare to the more commonly used stereotests. Therefore, the aim of the study was to determine the test-retest variability of four different measures of stereoacuity (TNO, Frisby, Lang Stereopad and Asteroid (Accurate STEReotest On a mobIle Device)) and to compare the stereoacuity measurements between the tests in an adult population. Methods: Stereoacuity was measured twice using TNO, Frisby, Lang Stereopad and Asteroid. Inclusion criteria included adult participants (18 years and older), no known ophthalmic condition and VA (Visual Acuity) equal to or better than 0.3 logMAR (Logarithm of the Minimum Angle of Resolution) with interocular difference of less than 0.2 logMAR. Bland-Altman analysis was used to assess agreement within and between stereotests. Differences in stereo thresholds were compared using signed Wilcoxon tests. Results: Fifty-four adults (male: 23 and female: 31) with VA equal to or better than 0.3 logMAR in either eye and interocular difference less than 0.2 logMAR were assessed (mean age: 38 years, SD: 12.7, range: 18-72). The test-retest variability of all the clinical stereotests, with the exception of the Lang Stereopad (p = .03, Wilcoxon signed-rank test), was clinically insignificant as the mean bias was equal or less than 0.06 log seconds of arc (equivalent to 1.15 seconds of arc). While the Asteroid test had the smallest variation between repeated measures (mean bias: -0.01 log seconds of arc), the Frisby and Lang Stereopad tests had the narrowest and widest limits of agreement respectively. When comparing results between tests, the biggest mean bias was between Frisby and Lang Stereopad (-0.62 log seconds of arc), and 64.8% and 31.5% of differences were in the medium (21-100" of arc) and larger (>100" of arc) ranges respectively. Conclusion: The TNO and Frisby tests have good reliability but measure stereoacuity over a narrower range compared to the Asteroid which shows less variation on repeated testing but has a larger testing range. The data reported here show varying degrees of agreement in a cohort of visually normal participants, and further investigation is required to determine if there is further variability when stereoacuity is reduced.

Using a Computerised Staircase and Incremental Optotype Sizes to Improve Visual Acuity Assessment Accuracy.

Background: Given the impact of visual acuity results on diagnosis and management, it is essential that the test is accurate, determined by factors such as test-retest variability. Standardisation improves accuracy, which can be performed via a computerised staircase methodology. Standard clinical tests with scoring of 0.02 per optotype implies an incremental score per optotype despite optotype size remaining constant on each line. The aim of this study is to establish if near continuous incremental optotype display and scoring improves test-retest variability compared to current testing methods. Methods: A computerised three up, one down adaptive staircase was used to display Kay Picture optotypes on an LCD monitor. Three methods of visual acuity assessment were undertaken: ETDRS, Kay Pictures and computerised Kay Pictures. Tests were performed twice under standard clinical conditions. Results: One hundred nineteen adults were tested. Test-retest variability for computerised Kay pictures was 0.01 logMAR (±0.04, p = 0.001). Good levels of agreement were observed for computerised Kay pictures in terms of test-retest variability, where the test had the smallest mean bias (0.01 logMAR compared to 0.03 and 0.08 logMAR for Kay Pictures and ETDRS respectively) and narrowest limits of agreement. Participants performed better in computerised Kay pictures than Kay Pictures by 0.03 logMAR, and better in ETDRS than computerised Kay pictures by 0.1 logMAR. Conclusion: Computerised Kay pictures exhibited a low test-retest variability, demonstrating it is reliable and repeatable. This repeatability measure is lower than the test-retest variability of the ETDRS and Kay Pictures tests.

Harmonization of [11C]raclopride brain PET images from the HR+ and HRRT: method development and validation in human subjects.

BACKGROUND: There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [11C]raclopride with older data. This typically means harmonizing data across different scanners. Previous harmonization studies have utilized either phantoms or human subjects, but the use of both phantoms and humans in one harmonization study is not common. The purpose herein was (1) to use phantom images to develop an inter-scanner harmonization technique and (2) to test the harmonization technique in human subjects. METHODS: To develop the harmonization technique (Experiment 1), the Iida brain phantom was filled with F-18 solution and scanned on the two scanners in question (HRRT, HR+, Siemens/CTI). Phantom images were used to determine the optimal isotropic Gaussian filter to harmonize HRRT and HR+ images. To evaluate the harmonization on human images (Experiment 2), inter-scanner variability was calculated using [11C]raclopride scans of 3 human subjects on both the HRRT and HR+ using percent difference (PD) in striatal non-displaceable binding potential (BPND) between HR+ and HRRT (with and without Gaussian smoothing). Finally, (Experiment 3), PDT/RT was calculated for test-retest (T/RT) variability of striatal BPND for 8 human subjects scanned twice on the HR+. RESULTS: Experiment 1 identified the optimal filter as a Gaussian with a 4.5 mm FWHM. Experiment 2 resulted in 13.9% PD for unfiltered HRRT and 3.71% for HRRT filtered with 4.5 mm. Experiment 3 yielded 5.24% PDT/RT for HR+. CONCLUSIONS: The PD results show that the variability of harmonized HRRT is less than the T/RT variability of the HR+. The harmonization technique makes it possible for BPND estimates from the HRRT to be compared to (and/or combined with) those from the HR+ without adding to overall variability. Our approach is applicable to all pairs of scanners still in service.

Predicting Global Test-Retest Variability of Visual Fields in Glaucoma.

PURPOSE: To model the global test-retest variability of visual fields (VFs) in glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Test-retest VFs from 4044 eyes of 4044 participants. METHODS: We selected 2 reliable VFs per eye measured with the Humphrey Field Analyzer (Swedish interactive threshold algorithm 24-2) within 30 days of each other. Each VF had fixation losses (FLs) of 33% or less, false-negative results (FNRs) of 20% or less, and false-positive results (FPRs) of 20% or less. Stepwise linear regression was applied to select the model best predicting the global test-retest variability from 3 categories of features of the first VF: (1) base parameters (age, mean deviation, pattern standard deviation, glaucoma hemifield test results, FPR, FNR, and FL); (2) total deviation (TD) at each location; and (3) computationally derived archetype VF loss patterns. The global test-retest variability was defined as root mean square deviation (RMSD) of TD values at all 52 VF locations. MAIN OUTCOME MEASURES: Archetype models to predict the global test-retest variability. RESULTS: The mean ± standard deviation of the root mean square deviation was 4.39 ± 2.55 dB. Between the 2 VF tests, TD values were correlated more strongly in central than in peripheral VF locations (intraclass coefficient, 0.66-0.89; P < 0.001). Compared with the model using base parameters alone (adjusted R2 = 0.45), adding TD values improved prediction accuracy of the global variability (adjusted R2 = 0.53; P < 0.001; Bayesian information criterion [BIC] decrease of 527; change of >6 represents strong improvement). Lower TD sensitivity in the outermost peripheral VF locations was predictive of higher global variability. Adding archetypes to the base model improved model performance with an adjusted R2 of 0.53 (P < 0.001) and lowering of BIC by 583. Greater variability was associated with concentric peripheral defect, temporal hemianopia, inferotemporal defect, near total loss, superior peripheral defect, and central scotoma (listed in order of decreasing statistical significance), and less normal VF results and superior paracentral defect. CONCLUSIONS: Inclusion of archetype VF loss patterns and TD values based on first VF improved the prediction of the global test-retest variability than using traditional global VF indices alone.

Determinants of Test Variability in Scotopic Microperimetry: Effects of Dark Adaptation and Test Indices.

Purpose: To test the effect of different dark adaptation conditions and reliability indices on the variability of two color scotopic microperimetry. Methods: We analyzed data from 22 consecutive visually healthy adults. Scotopic microperimetry was performed (Macular Integrity Assessment microperimeter, CenterVue, Padua, Italy) with two wavelength stimuli, cyan (505 nm) and red (627 nm), after a dark adaptation time of 10, 20, or 30 minutes. All tests were repeated twice to measure test-retest variability with Bland-Altman plots. We also provide a method to more accurately quantify the false-positive (FP) responses based on response data (button pressing) from the device, similar to FP responses used in standard static perimetry. Data on fixation stability (95% bivariate contour ellipse area) and blind spot responses were also extracted. Their relationship with measured sensitivity (in decibels) and test-retest variability was quantified through linear mixed effect models. Results: Dark adaptation had a significant effect on the sensitivity (dB) measured with the cyan stimulus (P < 0.001), but no effect on the red stimulus. Of the three metrics, the novel FP responses showed the best association with test-retest variability and was the only predictor consistently significant for all tests (P < 0.01). Conclusions: Dark adaptation protocols should be carefully standardized for scotopic testing, especially if a cyan stimulus is used. The proposed FP responses should be used to assess reliability of microperimetry examinations instead of other metrics. Translational Relevance: We developed a method to calculate a more accurate estimate of the FP responses using data available to all researchers, generalizable to all Macular Integrity Assessment microperimeter tests.

Calculation of test-retest variability in phase I/IIa clinical trials for Inherited Retinal Degenerations.

Background: Several novel treatments of inherited retinal degenerations have undergone phase I/IIa clinical trials with limited sample size, yet investigators must still determine if toxicity or an efficacy signal occurred or if the change was due to test-retest variability (TRV) of the measurement tool.Materials and Methods: Synthetic datasets were used to compare three types of TRV estimators under different sample sizes, mean drift, skewness, and number of baseline measurements.Results: Mixed effects models underestimated the standard deviation of measurement error (SDEM); the unbiased change score estimator method (UBS) was more accurate. The fixed effect model had less bias and smaller standard deviation than UBS if >2 baseline measurements. The change score estimator had no bias; other estimators introduced bias for lower variability. With sample size <10, all estimators had high variance. With sample size ≥10, the differences between methods were often minimal. The pooled estimator model did not capture drift, whereas a fixed effect regression or mixed effects models accounted for drift while maintaining an accurate measure of variance. With small sample sizes, the bootstrap estimates of SDEM were severe underestimates, while the jackknife estimates were mildly low but much better. The jackknife was more accurate for the unbiased change score method than for the pooled estimator.Conclusions: The ideal phase I/IIa study has ≥20 subjects and uses UBS or its fixed effect model generalization if >2 baseline measurements. With non-ideal study parameters, investigators should at least quantify the error estimate present in their data analysis.

Test-Retest Variability of Relative Tracer Delivery Rate as Measured by [11C]PiB.

PURPOSE: Moderate-to-high correlations have been reported between the [11C]PiB PET-derived relative tracer delivery rate R1 and relative CBF as measured using [15O]H2O PET, supporting its use as a proxy of relative CBF. As longitudinal PET studies become more common for measuring treatment efficacy or disease progression, it is important to know the intrinsic variability of R1. The purpose of the present study was to determine this through a retrospective data analysis. PROCEDURES: Test-retest data belonging to twelve participants, who underwent two 90 min [11C]PiB PET scans, were retrospectively included. The voxel-based implementation of the two-step simplified reference tissue model with cerebellar grey matter as reference tissue was used to compute R1 images. Next, test-retest variability was calculated, and test and retest R1 measures were compared using linear mixed effect models and a Bland-Altman analysis. RESULTS: Test-retest variability was low across regions (max. 5.8 %), and test and retest measures showed high, significant correlations (R2=0.92, slope=0.98) and a negligible bias (0.69±3.07 %). CONCLUSIONS: In conclusion, the high precision of [11C]PiB R1 suggests suitable applicability for cross-sectional and longitudinal studies.

Evaluation of a New Method to Track Changes in Vision at Home for Children Undergoing Amblyopia Treatment.

PURPOSE: A new amblyopia tracker app has been designed to provide parents with a method of monitoring a child's vision by presenting a single optotype size that the tester moves to identify the furthest distance the optotypes can be seen. The aim of this study is to evaluate this methodology in adults, comparing the findings to visual acuity (VA) measured with the iSight app and to determine the test retest variability. METHODS: Adults, aged 18-39 years, with no known eye condition and VA ≤ 0.7 logMAR were recruited. Bangerter filters were used to simulate amblyopia, where VA was reduced below 0.0 with an interocular difference of at least 0.2 logMAR. Testing for both apps was performed monocularly, with the test order being randomised. RESULTS: Data from 32 subjects were analysed. For the test retest variability analysis, paired t-tests showed no statistically significant difference between the tests for either eye, either app or the interocular acuity difference (p > 0.3 in all cases). Bland Altman plots showed similar limits of agreement between the two apps. When comparing measurements between the apps there was no statistically significant difference on the first or second test, either eye or the interocular acuity difference (p > 0.5 in all cases). CONCLUSION: The results support the theory that changing distance is a valid method of assessing VA as the measurements agree well with the standard approach of reducing optotype size. Test retest variability is similar between the two apps and there is good agreement between the measurements.

Test-retest variability of brain morphometry analysis: an investigation of sequence and coil effects.

BACKGROUND: Precise and reliable brain morphometry analysis is critical for clinical and research purposes. The magnetization-prepared rapid gradient echo (MPRAGE), multi-echo MPRAGE (MEMPRAGE) and magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) sequences have all been used to acquire brain structural images, but it is unclear which of these sequences is the most suitable for brain morphometry and whether the number of coil channels (20 or 32) affects scan precision. This study aimed to assess the impact of T1-weighted image acquisition variables (sequence and head coil) on the repeatability of resultant automated volumetric measurements. METHODS: Twenty-four healthy volunteers underwent back-to-back scanning protocols with three sequences and two different coils (i.e., six scanning conditions in total) presented in a randomized order in a single session. MorphoBox prototype and FreeSurfer were used for brain segmentation. Brain structures were divided into cortical and subcortical regions for more precise analysis. The acquired volume and thickness values were used to calculate test-retest variability (TRV) values. TRV values from the six different combinations were compared for total brain structures, total cortical structures, total subcortical structures, and every single structure. RESULTS: The median TRV value for all brain regions was 1.23% with MorphoBox and 3.14% with FreeSurfer. When using FreeSurfer results to compare the six combinations, for total brain structures volume and total cortical structures volume and thickness, the MEMPRAGE-32 channel combination showed significantly lower TRV values than the others (P<0.01). Similar results were observed with MorphoBox. For total subcortical structures, the MP2RAGE-32 channel combination showed the lowest TRV values with both MorphoBox (lower about 0.01% to 0.17%) and FreeSurfer analyses (lower about 0.02% to 0.37%). CONCLUSIONS: TRV values were generally low, indicating generally high reliability for every region. The MEMPRAGE sequence was the most reliable of the three sequences for total brain structures and cortical structures. However, MP2RAGE was the most reliable for subcortical structures. The 32-channel coil showed better repeatability results than the 20-channel coil.

Reproducibility of graph measures at the subject level using resting-state fMRI.

INTRODUCTION: Graph metrics have been proposed as potential biomarkers for diagnosis in clinical work. However, before it can be applied in a clinical setting, their reproducibility should be evaluated. METHODS: This study systematically investigated the effect of two denoising pipelines and different whole-brain network constructions on reproducibility of subject-specific graph measures. We used the multi-session fMRI dataset from the Brain Genomics Superstruct Project consisting of 69 healthy young adults. RESULTS: In binary networks, the test-retest variability for global measures was large at low density irrespective of the denoising strategy or the type of correlation. Weighted networks showed very low test-retest values (and thus a good reproducibility) for global graph measures irrespective of the strategy used. Comparing the test-retest values for different strategies, there were significant main effects of the type of correlation (Pearson correlation vs. partial correlation), the (partial) correlation value (absolute vs. positive vs. negative), and weight calculation (based on the raw (partial) correlation values vs. based on transformed Z-values). There was also a significant interaction effect between type of correlation and weight calculation. Similarly as for the binary networks, there was no main effect of the denoising pipeline. CONCLUSION: Our results demonstrated that normalized global graph measures based on a weighted network using the absolute (partial) correlation as weight were reproducible. The denoising pipeline and the granularity of the whole-brain parcellation used to define the nodes were not critical for the reproducibility of normalized graph measures.

The Test-Retest Variability of the COMPlog System in Participants with Induced Non-Normal Visual Acuity.

AIM: The aim of this study was to determine and compare test-retest variability (TRV) of the computerised visual acuity (VA) COMPlog system on participants with normal vision and non-normal vision induced by bangerter foils (BFs). METHODS: Twenty adult volunteers with VA of 0.100 logMAR or better in each eye and no eye conditions were included. Monocular VA data using the COMPlog system under five conditions-with plain Plano glasses (visually normal condition) and four pairs of Plano glasses with BF strengths of 0.6, 0.3, 0.2 and 0.1 (induced non-normal vision conditions)-were collected on two separate visits. To reduce bias, the eye tested and order of the BFs assessed were randomised. Data comparison was analysed using 2-factor ANOVA and paired t-tests and Bland Altman analysis to assess TRV. RESULTS: Mean VA score from the two visits was -0.072 ± 0.1 logMAR for Plano, 0.106 ± 0.1 logMAR for BF 0.6, 0.428 ± 0.1 logMAR for BF 0.3, 0.662 ± 0.09 logMAR for BF 0.2 and 0.850 ± 0.08 logMAR for BF 0.1. As BF density increased, VA score significantly worsened (p < 0.0001). Overall mean VA score from the first and second visit was 0.410 ± 0.4 logMAR and 0.379 ± 0.4 logMAR, respectively. This improvement was significant (p < 0.009). The 95% limits of agreement of the VA scores between testing conditions had a range of ±0.120 to ±0.220 logMAR. CONCLUSIONS: Increase in BF strength led to a worsened VA score. However, the COMPlog TRV under the visually normal and induced non-normal vision conditions were within a similar range (±0.120 to ±0.220 logMAR). VA significantly improved on the second visit, suggesting a possible learning effect, which could have a clinical impact.

Reliability of Semiautomated Kinetic Perimetry (SKP) and Goldmann Kinetic Perimetry in Children and Adults With Retinal Dystrophies.

PURPOSE: To investigate the precision of visual fields (VFs) from semiautomated kinetic perimetry (SKP) on Octopus 900 perimeters, for children and adults with inherited retinal degenerations (IRDs). Goldmann manual kinetic perimetry has long been used in the diagnosis and follow-up of these patients, but SKP is becoming increasingly common. Octopus VFs (OVFs) and Goldmann VFs (GVFs) were both mapped on two occasions. METHODS: Nineteen females and 10 males with IRDs were tested on OVFs and GVFs, with two targets per test (V4e and one smaller target). Tests were performed in the same (randomized) order at two visits about 1 week apart. The VFs were digitized to derive isopter solid angles. Comparisons, within and between visits, were performed with paired t-tests and Bland-Altman plots. RESULTS: Median age was 20 years (range, 7-70; 10 participants aged ≤17 years old). There were no significant differences in solid angles between OVFs and GVFs (P ≥ 0.06) or between the two visits' solid angles on either perimeter (P ≥ 0.30). Between-visit test-retest variability for GVFs and OVFs was similar (P ≥ 0.73), with median values of approximately 9% to 13%. Overall variability was lower for children than adults (medians of 7.5% and 12.8%, respectively). CONCLUSIONS: Octopus SKP and Goldmann perimetry produced VFs of similar size and variability. TRANSLATIONAL RELEVANCE: Our study indicates that SKP provides a viable alternative to traditional Goldmann perimetry in clinical trials or care involving both children and adults with IRDs.

18F-JNJ-64413739, a Novel PET Ligand for the P2X7 Ion Channel: Radiation Dosimetry, Kinetic Modeling, Test-Retest Variability, and Occupancy of the P2X7 Antagonist JNJ-54175446.

The P2X7 receptor (P2X7R) is an adenosine triphosphate-gated ion channel that is predominantly expressed on microglial cells in the central nervous system. We report the clinical qualification of P2X7-specific PET ligand 18F-JNJ-64413739 in healthy volunteers, including dosimetry, kinetic modeling, test-retest variability, and blocking by the P2X7 antagonist JNJ-54175446. Methods: Whole-body dosimetry was performed in 3 healthy male subjects by consecutive whole-body PET/CT scanning, estimation of the normalized cumulated activity, and calculation of the effective dose using OLINDA (v1.1). Next, 5 healthy male subjects underwent a 120-min dynamic 18F-JNJ-64413739 PET/MRI scan with arterial blood sampling to determine the appropriate kinetic model. For this purpose, 1- and 2-tissue compartment models and Logan graphic analysis (LGA) were evaluated for estimating regional volumes of distribution (VT). PET/MRI scanning was repeated in 4 of these subjects to evaluate medium-term test-retest variability (interscan interval, 26-97 d). For the single-dose occupancy study, 8 healthy male subjects underwent baseline and postdose 18F-JNJ-64413739 PET/MRI scans 4-6 h after the administration of a single oral dose of JNJ-54175446 (dose range, 5-300 mg). P2X7 occupancies were estimated using a Lassen plot and regional baseline and postdose VTResults: The average (mean ± SD) effective dose was 22.0 ± 1.0 µSv/MBq. The 2-tissue compartment model was the most appropriate kinetic model, with LGA showing very similar results. Regional 2-tissue compartment model VT values were about 3 and were rather homogeneous across all brain regions, with slightly higher estimates for the thalamus, striatum, and brain stem. Between-subject VT variability was relatively high, with cortical VT showing an approximate 3-fold range across subjects. As for time stability, the acquisition time could be reduced to 90 min. The average regional test-retest variability values were 10.7% ± 2.2% for 2-tissue compartment model VT and 11.9% ± 2.2% for LGA VT P2X7 occupancy approached saturation for single doses of JNJ-54175446 higher than 50 mg, and no reference region could be identified. Conclusion:18F-JNJ-64413739 is a suitable PET ligand for the quantification of P2X7R expression in the human brain. It can be used to provide insight into P2X7R expression in health and disease, to evaluate target engagement by P2X7 antagonists, and to guide dose selection.