Test-retest Variability Research Articles

P-787. Potential Impact of Repeating Unexpected Positive Interferon Gamma Release Assays

Abstract Background Interferon gamma release assays (IGRAs) are more specific for tuberculosis infection than the tuberculin skin test but also have higher test-retest variability. False positive tests may occur in low prevalence populations. As such, repeating unexpected positive tests (positive tests in patients without exposure risk) is recommended.Table:Initial and repeat IGRA results Methods We performed a retrospective electronic record review of all patients for whom a QuantiFERON (IGRA) was performed in Duke University Health System between 10/1/2014-5/3/2024. We examined patterns of repeat testing and ascertained the potential clinical impact of repeat testing. Results In total, 59,485 IGRAs were performed on 49,850 patients during the study period. 7,076 patients had repeat IGRA testing (median 2 IGRAs, range 2-9). Of these, 6137 had negative, 297 positive, and 642 indeterminate results on the first test. When repeat testing was performed, 743 (11%) patients had a different result on the second test (Table). Of patients with initial positive results, 104/297 (35%) had a negative result on the second test, which was performed a median of 110 days later (IQR 16-420 days). 86 patients had a negative first test but a positive second test; of these, 38 had a third test performed that was negative in 27 (71%) and positive in 11 (29%). Conclusion In a low-prevalence setting, repeating positive IGRA tests potentially avoided unnecessary preventive treatment in over a third of patients with an initial positive test and in two-thirds of patients with a prior negative test. Disclosures Nicholas A. Turner, MD, MHSc, PDI: Research contract|Purio Labs: Research contract

Test-retest repeatability of intravoxel incoherent motion (IVIM) measurements in the cervical cord

Abstract Intravoxel incoherent motion (IVIM) measurements allow to probe tissue microcirculation non-invasively. Spinal cord perfusion has been shown to be altered following different neurological pathologies. A non-invasive imaging protocol to assess perfusion in the cervical cord is therefore clinically relevant. This work aimed at assessing the reliability of IVIM parameters sensitive to perfusion changes in the cervical cord by determining the test-retest variability across subjects and different post-processing fitting algorithms. IVIM test-retest scans were acquired in the cervical cord (C1-C3) of 10 healthy subjects on a 3T MRI scanner, with a 15-minute break in-between. IVIM parameters, including microvascular volume fraction (F), pseudo-diffusion coefficient (D*), blood flow-related coefficient (F⋅D*), and diffusion coefficient (D), were derived using voxel-wise and region of interest (ROI)-wise fits. The reliability of each IVIM parameter was determined with coefficients of variation (CV), intraclass correlation coefficients (ICC), Bland-Altman analysis and linear regression. To assess the effects of the different fitting approaches, a two-way repeated-measures analysis of variance (ANOVA) was conducted on the CVs calculated across fitting algorithms. Mean CVs of IVIM parameters calculated across subjects using the voxel-wise fit was lower in the white matter (WM) and grey matter (GM): (WM: 2.6% to 15.6%; GM: 2.2% to 16.4%) compared with those calculated using the ROI-wise fit approach (WM: 4.5% to 32.2%; GM: 3.4% to 53.4%). The voxel-wise fit in the WM yielded higher ICC values (good-to-excellent, 0.71 – 0.97) compared to the ROI-wise fit approach (poor-to-excellent, 0.49 – 0.90). IVIM parameters, derived using the voxel-wise fitting approach, demonstrated a high reliability in the cervical cord. Results highlight the high variability of IVIM parameter values depending on the fitting approach, underlining the importance of characterizing the reliability of IVIM acquisition and fitting configuration in the relevant organ of interest. Robust IVIM metrics using a voxel-wise one-step approach, observed across scans and subjects, can facilitate studies targeting perfusion impairment and pave the way to future clinical trials assessing perfusion impairment as a potential quantitative biomarker.

Validity and Reliability of the Spanish Version of Godin-Shephard Leisure-Time Physical Activity Questionnaire in Prostate Cancer Patients.

Prostate cancer is highly prevalent in Spanish men. Although physical activity has benefits on several factors in prostate cancer survivors, this is diminished after medical oncology treatment. Cancer-related fatigue is one of the main barriers to physical activity, leading to a decrease in activity levels in these patients. Therefore, it is essential to assess physical activity in an efficient and simple way in order to design rehabilitation programmes for this population. The aim was to translate and adapt the Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) for Spanish-speaking prostate cancer patients and to assess its validity and reliability using the International Physical Activity Questionnaire (IPAQ) as a reference standard. Following Beaton's guidelines, the GSLTPAQ was back-translated and cross-culturally adapted. Validity and reliability were assessed with a sample of thirty prostate cancer patients. Internal consistency and test-retest variability were also evaluated. The Spanish GSLTPAQ demonstrated excellent validity, with high correlations with the IPAQ for light (r = 0.924), moderate (r = 0.931), and vigorous activities (r = 0.882). Internal consistency was strong (Cronbach's alpha: 0.845-0.950). Test-retest reliability showed strong intraclass correlation coefficients (ICCs) for all activity levels, indicating good reliability. The Spanish version of the GSLTPAQ is a valid and reliable tool for assessing physical activity in prostate cancer patients. It shows strong correlations with the IPAQ, excellent internal consistency, and test-retest reliability.

Effects of acute hydration changes on cardiovascular magnetic resonance native T1 and T2 mapping.

Changes in hydration status may affect myocardial native T1 and T2 values and influence the clinical interpretation. We aimed to assess the impact of acute preload augmentation on native T1 and T2. Cardiovascular magnetic resonance (CMR) native T1 and T2 mapping were performed twice on the same day in 20 healthy participants before and after an acute preload augmentation by a 2-liter intravenous infusion of isotonic sodium chloride (0.9%). Test-retest reproducibility was evaluated in 30 healthy participants with two consecutive CMR examinations on the same day. Sixteen participants were included in both substudies. In the 20 healthy participants undergoing acute preload augmentation (55% males, mean age (interquartile range [IQR]) 43 [29-51] years), native T1 increased with 17 ms (95% confidence interval [CI] 7 to 26; p = 0.001), T2 with 1.7 ms (95% CI 0.8 to 2.4; p < 0.001), and blood T1 with 46 ms (95% CI 28 to 65; p < 0.001). Test-retest variability in 30 healthy participants (47% males, median age 43 [28-52] years) showed 95% limits of agreement (LOA) of ± 26 ms for native T1, ± 2.1 ms for T2, and ± 57 ms for blood T1. In the 16 participants included in both substudies, the mean differences in changes post-infusion versus test-retest were 22 ms (95% CI 8 to 36; p = 0.01) for native T1, 1.9 ms (95% CI 0.9 to 2.9; p = 0.001) for T2, and 62 ms (95% CI 32 to 91; p < 0.001) for blood T1. Native T1 and T2 values increased following acute preload augmentation. However, the changes were within the 95% LOA of the test-retest reproducibility.

Test–retest performance of [18F]MK-6240 tau burden and relative delivery indices in cognitively normal older subjects using PET/MRI

Abstract Accurate interpretation of quantitative positron emission tomography (PET) outcomes hinges on understanding the test–retest variability (T-RT). Previous studies of the tau-PET ligand [18F]MK-6240 reported adequate T-RT performance of tau burden estimates over a short-term 21-day and over a longer-term 6-month T-RT period, primarily involving Alzheimer’s disease (AD) and cognitively normal (CN) subjects, respectively. However, several T-RT characteristics have not yet been reported, particularly in older CN (oCN) subjects. Here, we investigate the short-term T-RT performance of dynamic [18F]MK-6240 outcomes in a group largely consisting of oCN. We report T-RT for uptake in potential reference regions, for extracerebral off-target signal, and for estimates of tau burden and relative delivery indices in tau-bearing target regions. Eight participants (7 oCN, 1 AD) underwent baseline dynamic [18F]MK-6240 PET/MRI (Biograph mMR) and a retest follow-up PET/MRI scan within approximately 3 weeks. T-RT was evaluated using absolute percentage differences and intraclass correlation coefficients (ICC) in three groups of regions: (1) potential reference regions using standardized-uptake values 90–110 minutes post-injection (SUV90–110); (2) target regions using SUV ratios (SUVR90–110), distribution volume ratios (DVR), and relative delivery (R1); and (3) extracerebral region using SUVR90–110. A voxel-based partial volume correction (PVC) was applied. T-RT was evaluated with and without PVC. In oCN subjects, the SUV90–110 T-RT in the evaluated reference regions ranged from 6 to 11% (ICC &amp;gt; 0.9); target region T-RT was similar for SUVR90–110 (4–9%, ICC: 0.62–0.97), DVR (3–10%, ICC: 0.66–0.92), and R1 (3–14%, ICC: 0.52–0.97). PVC had minimal impact on reference region SUV90–110 T-RT, but increased target region T-RT variability (SUVR90–110: 10–26%; DVR: 6–22%; R1: 4–20%). Extracerebral SUVR90–110 exhibited higher T-RT variability (~12%, ICC: 0.85) than other target regions (average 6%) and increased to ~15% after PVC. Our findings are consistent with previous reports and provide further evidence of acceptable [18F]MK-6240 T-RT in low-signal oCN subjects. Our results suggest [18F]MK-6240 is suitable for detecting early tau deposition and longitudinal changes over time, and further support the viability of [18F]MK-6240 R1 to evaluate longitudinal changes in perfusion. PVC increased T-RT variability in tau burden and R1 outcomes. Notably, the extracerebral signal exhibited higher T-RT variability than other target and reference regions and may affect their signal.

Endpoint Selection in Randomized Clinical Trials for Hypertrophic Cardiomyopathy.

Randomized clinical trials (RCTs) for hypertrophic cardiomyopathy (HCM) have long been challenging caused by the condition's rarity, low event rates, and diverse clinical presentations. However, recent advances in targeted therapies have sparked increased interest in HCM research. Despite this, designing effective RCTs remains complex, particularly in identifying clinically meaningful endpoints. HCM, often linked to sequence variation in sarcomeric protein genes like MYH7 and MYBPC3, exhibits varied phenotypic expressions that influence disease progression and treatment responses. This genetic variability underscores the need for personalized approaches in clinical trials. Emerging gene therapies, such as CRISPR/Cas9, show promise in addressing these genetic factors. A major challenge in HCM RCTs is ensuring that endpoints are both statistically and clinically significant, given issues like test-retest variability and missing data. Primary endpoints often focus on symptom relief and functional improvement, while secondary and exploratory endpoints provide broader insights into treatment effects. Regulatory authorities are increasingly open to a wider range of endpoints, including patient-reported outcomes and functional measures, although the cost-risk balance is crucial, especially for high-risk interventions. Future HCM RCTs may incorporate hard clinical endpoints such as heart failure hospitalization, atrial fibrillation recurrence, and all-cause mortality, offering a more comprehensive evaluation of treatment efficacy. Integrating genetic insights and advanced technologies will be essential to improving trial design and enhancing patient outcomes in HCM.

Test-retest variability of mesopic microperimetry-associated parameters in patients with retinitis pigmentosa: REPEAT Study Report No. 2.

Understanding test-retest variability (TRV) of mesopic microperimetry is critical for defining meaningful treatment effects in retinitis pigmentosa (RP) trials. This study uniquely evaluates intra- and intervisit TRV and coefficients of repeatability (CoRs) for microperimetry parameters in RP patients with varying best-corrected visual acuity (BCVA) levels. In this single-centre prospective cohort study, RP patients were assessed on two visits, 14.0 days apart. Patients were grouped by BCVA: low (≤20/50 Snellen; ≥0.4 logMAR) or moderate (>20/50 Snellen; <0.4 logMAR). Using Bland-Altman analyses, the CoRs for intra- and intervisit variability were determined for pointwise (dB), mean (dB), and volume sensitivity (dB*deg2) on mesopic microperimetry. Intravisit CoRs for mean, volume, and pointwise sensitivity were 1.7 dB, 353.2 dB*deg2, and 8.6 dB, respectively, in the low-BCVA group (n = 32), and 0.9 dB, 254.5 dB*deg2, and 7.3 dB in the moderate-BCVA group (n = 15). Intervisit CoRs for mean, volume, and pointwise sensitivity were 2.4 dB, 355.2 dB*deg2, and 10.2 dB in the low-BCVA group (n = 31). The moderate-BCVA group (n = 16) showed smaller CoRs of 1.6 dB, 386.8 dB*deg2, and 7.7 dB for mean, volume, and pointwise sensitivity. BCVA and mean sensitivity, but not fixation stability, are predictors of TRV for volume sensitivity. Due to significant TRV, pointwise sensitivity is an unreliable endpoint for RP patients, irrespective of BCVA. Mean sensitivity is suitable as an endpoint when BCVA is relatively preserved. Volume sensitivity provides additional spatial information, and shows promise as a clinical endpoint for assessing macular sensitivity changes on mesopic microperimetry in patients with RP.

Improving MR axon radius estimation in human white matter using spiral acquisition and field monitoring.

To compare MR axon radius estimation in human white matter using a multiband spiral sequence combined with field monitoring to the current state-of-the-art echo-planar imaging (EPI)-based approach. A custom multiband spiral sequence was used for diffusion-weighted imaging at ultra-high -values. Field monitoring and higher order image reconstruction were employed to greatly reduce artifacts in spiral images. Diffusion weighting parameters were chosen to match a state-of-the art EPI-based axon radius mapping protocol. The spiral approach was compared to the EPI approach by comparing the image signal-to-noise ratio (SNR) and performing a test-retest study to assess the respective variability and repeatability of axon radius mapping. Effective axon radius estimates were compared over white matter voxels and along the left corticospinal tract. Increased SNR and reduced artifacts in spiral images led to reduced variability in resulting axon radius maps, especially in low-SNR regions. Test-retest variability was reduced by a factor of approximately 1.5 using the spiral approach. Reduced repeatability due to significant bias was found for some subjects in both spiral and EPI approaches, and attributed to scanner instability, pointing to a previously unknown limitation of the state-of-the-art approach. Combining spiral readouts with field monitoring improved mapping of the effective axon radius compared to the conventional EPI approach.

Inter-Vendor differences in speckle tracking strain - A ten year follow-up on the Strain Standardization Task Force Inter-Vendor Comparison Study

Abstract Background Global longitudinal strain (GLS) derived from two-dimensional speckle-tracking echocardiography is feasible and accurate. Nonetheless, in 2013, the Inter-Vendor Comparison Study showed significant differences of measurement results among vendors. In order to make tracking-based strain imaging a clinically accepted and useful parameter, it is of outmost importance to have interchangeable and accurate measurement results from all vendors. Purpose To investigate if the efforts of the EACVI/ASE/Industry Task Force to Standardize Deformation Imaging have led to a reduction of inter-vendor differences during the past ten years. Methods In an unique setting, in one single room, 372 echocardiographic examinations were performed in sixty-two subjects (50 male, age 56.1 ± 16.98) with a wide range of left ventricular (LV) function (ejection fraction from 30% to 64%) using ultrasound systems from six manufacturers. Each subject was scanned consecutively on all machines by the same assigned experienced sonographer. For each subject two image sets of LV apical views were acquired in order to assess reproducibility in a true test-retest setting. We assessed mean GLS (GLSAV) as average peak systolic global strain from the three apical views on five vendor-specific and five vendor-independent software solutions. We measured endocardial and mid-/full-wall GLS. Since there is no gold standard method to measure GLS, we compared GLSAV of each vendor to the average of the GLS values only from vendors that provide tracking software solutions (SWS) for clinical use. Results For both endocardial (Figure 1) and mid-/full-wall (Figure 2) GLS measurements from clinical SWS were comparable and within a very narrow range (mean GLS of vendors 17.25 ± 0.3% and 15.36 ± 0.3% respectively). The maximum absolute difference between all SWS was 4.1% and 4.9% strain units for endocardial and mid-/full-wall GLS respectively. GLSAV of each software versus the mean of clinical SWS showed significant correlation for most of the companies (r² &amp;gt;0.8, p&amp;lt;0.001). Test-retest variability of GLS measurements expressed as relative mean error was good and lower than for LV ejection fraction (6.3% on average for mean GLS and 7% for LV ejection fraction, p&amp;gt;0.05). Conclusions Our data show a substantial inter-vendor bias in GLS measurements. Nevertheless, in contrast to the situation ten years ago, companies that provide tracking software solutions for clinical use provide now very similar GLS values. In addition, most companies do now allow mid-/full-wall tracking. Our data indicate that the efforts of the strain standardization task force have been fruitful. A continuing effort is needed until all software providers adhere to the task force consensus recommendations.Figure 1Figure 2

Exploring Scotopic Microperimetry as an Outcome Measure in Choroideremia.

Choroideremia is an X-linked outer retinal degeneration. Early symptoms include nyctalopia and progressive visual field loss, but visual acuity is preserved until late disease stages. Dark-adapted two-color fundus-controlled perimetry (also known as scotopic microperimetry) has been developed to enable spatial assessment of rod and cone photoreceptor function. This study explores the use of scotopic microperimetry in patients with choroideremia. Twenty patients with choroideremia and 21 age-matched healthy controls completed visual acuity and scotopic microperimetry testing, which used the Scotopic Macular Integrity Assessment (S-MAIA) microperimeter. A subset of participants completed repeat scotopic testing to enable Bland-Altman repeatability analyses. Test reliability was assessed using fixation stability, fixation losses, and assessment of the rod-free zones. Pointwise sensitivity, mean sensitivity, and volume sensitivity indices were analyzed. False positive responses were the main source of poor test reliability, indicated by stimuli responses in the physiological blind spot and lack of rod-free mapping. Scotopic cyan and red sensitivities were significantly reduced in choroideremia participants (n = 17) compared to healthy controls (n = 16) (P < 0.01, Mann-Whitney U test). Scotopic cyan sensitivity was statistically lower than scotopic red sensitivity in both healthy controls and choroideremia (P < 0.01, Wilcoxon signed rank test). Interpretation of scotopic cyan-red differences should be used with caution due to high test-retest variability. Scotopic microperimetry could be a useful outcome measure in patients with early choroideremia. Careful selection of test grid design and sensitivity indices is required. Scotopic microperimetry may be a useful outcome measure in clinical trials for patients with early stage choroideremia.

Corneal densitometry measurements comparison between anterior segment OCT and scheimpflug imaging

PurposeTo evaluate and compare the repeatability of corneal densitometry (CD) measurements obtained using both an anterior-segment optical coherence tomography (AS-OCT) device and a Scheimpflug camera system, while also assessing the level of agreement. The study also sought to investigate the correlation of CD with age, gender, and central corneal thickness (CCT) in normal eyes.MethodsCD measurements were obtained using the Casia 2 and the Pentacam AXL Wave. Data were collected on Total Corneal Densitometry and 4 concentric corneal annular areas, these are referred to as zone 1, denoting the central area, through to zone 4, designating the outermost peripheral region. Repeatability was assessed using intra-session test–retest variability, coefficient of variation (CoV), and intraclass correlation coefficient (ICC). The agreement was evaluated using Bland–Altman plots. Correlation analysis was performed between CD, age, gender, and CCT.ResultsThe study included 96 healthy volunteers. The Casia 2 demonstrated high repeatability with ICC values exceeding 0.9 in all the corneal zones and lower CoV values compared to the Pentacam AXL Wave (ranging from 1.07% to 2.25% for Casia 2 and from 1.91% to 6.89% for Pentacam).95% LoA were within ± 2 standard deviation from the average mean except from zone 1 (± 2.42).However, the measurements showed a consistent bias among all the corneal zones. CD values were positively correlated with age, except for zone 1 with the Pentacam (p = 0.083).ConclusionsThe findings suggest that the Casia 2 can be a reliable tool for assessing corneal transparency in healthy individuals, however its measurements are not interchangeable with those provided by the Pentacam. The AS-OCT device may be more sensitive in detecting subtle age-related changes in CD within the central zone.

Diagnostic Power and Reproducibility of Objective Perimetry in Glaucoma.

An objective perimetry method provides four 30-2 style reports in 8 minutes. These comprise sensitivity and delay reports for both eyes. A combined report format shows comparable diagnostic power to two forms of automated perimetry. To compare objective perimetry with two forms of standard automated perimetry (SAP) in glaucoma. The study cohort contained 40 persons with glaucoma (PwG) and 94 normal control subjects. The PwG had both perimetric and pre-perimetric eyes. Multifocal pupillographic objective perimetry was performed with the objectiveField Analyser® (OFA®), which independently assesses the visual fields of both eyes concurrently. Its OFA30 test assessed the central ±30°, and the OFA15 test assessed the central ±15°, both providing 30-2 style reports. The OFA tests were repeated two weeks apart to assess test-retest variability (TRV). OFA was compared with Matrix and HFA-SITA fast 24-2 threshold testing. Diagnostic power was quantified as area under receiver operating characteristic curves (AUROC). Test durations, Mean Defects and Pattern Standard Deviations of the 4 tests were compared. At a median of 4.09±0.02 minutes/eye the OFA tests were quicker than SAP (all P≤0.0001), 2 minutes/eye if OFA per-region sensitivities and delays are considered separately. The %AUROCs for OFA, Matrix and HFA were not significantly different, averaging 93±3% (mean±SD) in perimetric eyes, and 73±6% in pre-perimetric eyes. For moderate to severe fields OFA TRV was less than published results for SAP. OFA30 mean defects were significantly correlated between repeats (r=0.91), and with OFA15 (r=0.93, both P<0.0001). OFA provides extra functional measures in the form of per-region delays, and between-eye asymmetries. Both the OFA wide-field and macular tests provided comparable diagnostic power to SAP and better TRV in damaged eyes.

Accuracy of MSBase criteria to diagnose secondary progressive multiple sclerosis in large German real-world patient cohort

Background and ObjectivesAccurate diagnosis of secondary progression in multiple sclerosis (MS) remains a challenge since standardized criteria are missing. In 2016, the MSBase registry presented an algorithm that enabled the diagnosis of secondary progressive multiple sclerosis (SPMS) more than three years earlier compared to diagnosis by neurologists. This work aimed to test whether this approach is equally effective in a real-world cohort of MS patients. MethodsThis longitudinal retrospective study analyzed clinical data of outpatients with MS recorded until October 2020 in the NeuroTransData registry, a Germany-wide network of 153 certified neurologists. Patient data had been captured in time during clinical visits employing a defined standardized clinical data set in the webbased NeuroTransData patient management platform DESTINY®. The time between the diagnosis of relapsing-remitting multiple sclerosis (RRMS) to SPMS onset was compared with one determined using MSBase criteria (MSBC). Group 1 consisted of patients diagnosed with SPMS during the observation period, whereas group 2 included RRMS patients who did not convert to SPMS during the observation period. ResultsOf 21,281 patients with MS included in our registry, 194 and 9506 patients were allocated to groups 1 and 2, respectively. 10.3% of patients with RRMS were diagnosed with SPMS simultaneously, whereas 60.8% were diagnosed with SPMS at least 3 months earlier by treating neurologists compared to the MSBC. In group 1, the MSBC showed a low sensitivity of 32.0% and an accuracy of 61.4% but a high specificity of 89.6%. In group 2, the MSBC identified 7.8% of patients with SPMS at some point during the observation time. Moreover, test-retest variability remains a challenge since 29.4% of patients diagnosed with SPMS by treating physicians did not fulfil the MSBC at a later point in time. DiscussionThese results are inconsistent with earlier SPMS diagnosis using the MSBC compared to clinical diagnosis by treating physicians. Therefore, there remains a need for an operational, structured, and validated approach to SPMS diagnosis.

Noninvasive quantification of [18F]SynVesT-1 binding using simplified reference tissue model 2.

[18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions. Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated. The 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates. Our findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.

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

PurposeMultidrug 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.MethodsThirteen 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.ResultsMean 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.ConclusionLAFOV 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 registrationEudraCT 2021-006348-29. Registered 15 December 2021.

Preparation-based B mapping in the heart using Bloch-Siegert shifts.

To develop and evaluate a robust cardiac mapping sequence at 3 T, using Bloch-Siegert shift (BSS)-based preparations. A longitudinal magnetization preparation module was designed to encode . After magnetization tip-down, off-resonant Fermi pulses, placed symmetrically around two refocusing pulses, induced BSS, followed by tipping back of the magnetization. Bloch simulations were used to optimize refocusing pulse parameters and to assess the mapping sensitivity. Relaxation-induced error was simulated for various / times. The effective mapping range was determined in phantom experiments, and maps were compared to the conventional BSS method and subadiabatic hyperbolic-secant 8 (HS8) pulse-sensitized method. Cardiac maps were acquired in healthy subjects, and evaluated for repeatability and imaging plane intersection consistency. The technique was modified for three-dimensional (3D) acquisition of the whole heart in a single breath-hold, and compared to two-dimensional (2D) acquisition. Simulations indicate that the proposed preparation can be tailored to achieve high mapping sensitivity across various ranges, with maximum sensitivity at the upper range. / -induced bias did not exceed 5.2 . Experimentally reproduced sensitization closely matched simulations for (mean difference 0.031 0.022, compared to 0.018 0.025 in the HS8-sensitized method), and showed 20-fold reduction in the standard deviation of repeated scans, compared with conventional BSS mapping, and an equivalent 2-fold reduction compared with HS8-sensitization. Robust cardiac map quality was obtained, with an average test-retest variability of 0.027 0.043 relative to normalized magnitude, and plane intersection bias of 0.052 0.031. 3D acquisitions showed good agreement with 2D scans (mean absolute deviation 0.055 0.061). BSS-based preparations enable robust and tailorable 2D/3D cardiac mapping at 3 T in a single breath-hold.

Investigation of [11C]carfentanil for mu opioid receptor quantification in the rat brain

[11C]Carfentanil ([11C]CFN) is the only selective carbon-11 labeled radiotracer currently available for positron emission tomography (PET) imaging of mu opioid receptors (MORs). Though used extensively in clinical research, [11C]CFN has not been thoroughly characterized as a tool for preclinical PET imaging. As we were occasionally observing severe vital sign instability in rat [11C]CFN studies, we set out to investigate physiological effects of CFN mass and to explore its influence on MOR quantification. In anesthetized rats (n = 15), significant dose-dependent PCO2 increases and heart rate decreases were observed at a conventional tracer dose range (IV, > 100 ng/kg). Next, we conducted baseline and retest [11C]CFN PET scans over a wide range of molar activities. Baseline [11C]CFN PET studies (n = 27) found that nondisplaceable binding potential (BPND) in the thalamus was positively correlated to CFN injected mass, demonstrating increase of MOR availability at higher injected CFN mass. Consistently, when CFN injected mass was constrained < 40 ng/kg (~ 10% MOR occupancy in rats), baseline MOR availability was significantly decreased. For test–retest variability (TRTV), better reproducibility was achieved by controlling CFN injected mass to limit the difference between scans. Taken together, we report significant cardiorespiratory depression and a paradoxical influence on baseline MOR availability at conventional tracer doses in rats. Our findings might reflect changes in cerebral blood flow, changes in receptor affinity, or receptor internalization, and merits further mechanistic investigation. In conclusion, rat [11C]CFN PET requires stringent quality assurance of radiotracer synthesis and mass injected to avoid pharmacological effects and limit potential influences on MOR quantification and reproducibility.

Implementing ABCD studyⓇ MRI sequences for multi-site cohort studies: Practical guide to necessary steps, preprocessing methods, and challenges

Large multi-site studies that combine magnetic resonance imaging (MRI) data across research sites present exceptional opportunities to advance neuroscience research. However, scanner or site variability and non-standardised image acquisition protocols, data processing and analysis pipelines can adversely affect the reliability and repeatability of MRI derived brain measures. We implemented a standardised MRI protocol based on that used in the Adolescent Brain Cognition Development (ABCD)Ⓡ study in two sites, and across four MRI scanners.Twice repeated measurements of a single healthy volunteer were obtained in two sites and in four 3T MRI scanners (vendors: Siemens, Philips, and GE). Imaging data included anatomical scans (T1 weighted, T2 weighted), diffusion weighted imaging (DWI) and resting state functional MRI (rs-fMRI). Standardised containerized pipelines were utilised to pre-process the data and different image quality metrics and test-retest variability of different brain metrics were evaluated.The implementation of the MRI protocols was possible with minor adjustments in acquisition (e.g. repetition time (TR), higher b-values) and exporting (DICOM formats) of images due to different technical performance of the scanners. This study provides practical insights into the implementation of standardised sequences and data processing for multisite studies, showcase the benefits of containerised preprocessing tools, and highlights the need for careful optimisation of multisite image acquisition.

Simultaneous assessment of blood flow and myelin content in the brain white matter with dynamic [11C]PiB PET: a test-retest study in healthy controls.

Exploring the relationship between oxygen supply and myelin damage would benefit from a simultaneous quantification of myelin and cerebral blood flow (CBF) in the brain's white matter (WM). To validate an analytical method for quantifying both CBF and myelin content in the WM using dynamic [11C]PiB positron emission tomography (PET). A test-retest study was performed on eight healthy subjects who underwent two consecutive dynamic [11C]PiB-PET scans. Three quantitative approaches were compared: simplified reference tissue model 2 (SRTM2), LOGAN graphical model, and standardized uptake value ratio (SUVR). The sensitivity of methods to the size of the region of interest was explored by simulating lesion masks obtained from 36 subjects with multiple sclerosis. Reproducibility was assessed using the relative difference and interclass correlation coefficient. Repeated measures correlations were used to test for cross-correlations between metrics. Among the CBF measures, the relative delivery (R1) of the simplified reference tissue model 2 (SRTM2) displayed the best reproducibility in the white matter, with a strong influence of the size of regions analyzed, the test-retest variability being below 10% for regions above 68 mm3 in the supratentorial white matter. [11C]PiB PET-derived proxies of CBF demonstrated lower perfusion of white matter compared to grey matter with an overall ratio equal to 1.71 ± 0.09 when the SRTM2-R1 was employed. Tissue binding in the white matter was well estimated by the Logan graphical model through estimation of the distribution volume ratio (LOGAN-DVR) and SRTM2 distribution volume ratio (SRTM2-DVR), with test-retest variability being below 10% for regions exceeding 106 mm3 for LOGAN-DVR and 300 mm3 for SRTM2-DVR. SRTM2-DVR provided a better contrast between white matter and grey matter. The interhemispheric variability was also dependent on the size of the region analyzed, being below 10% for regions above 103 mm3 for SRTM2-R1 and above 110 mm3 for LOGAN-DVR. Whereas the 1 to 8-minute standardized uptake value ratio (SUVR1-8) showed an intermediary reproducibility for CBF assessment, SUVR0-2 for perfusion or SUVR50-70 for tissue binding showed poor reproducibility and correlated only mildly with SRTM2-R1 and LOGAN-DVR estimations respectively. [11C]PiB PET imaging can simultaneously quantify perfusion and myelin content in WM diseases associated with focal lesions. For longitudinal studies, SRTM2-R1 and DVR should be preferred over SUVR for the assessment of regional CBF and myelin content, respectively. European Union Clinical Trials Register EUDRACT; EudraCT Number: 2008-004174-40; Date: 2009-03-06; https//www.clinicaltrialsregister.eu ; number 2008-004174-40.

Effects of Tympanic Membrane Electrodes on Sound Transmission From the Ear Canal to the Middle and Inner Ears.

The first objective of the study was to compare approaches to eardrum electrode insertion as they relate to the likelihood of introducing an acoustic leak between the ear canal and eartip. A common method for placing a tympanic membrane electrode involves securing the electrode in the canal by routing it underneath a foam eartip. This method is hypothesized to result in a slit leak between the canal and foam tip due to the added bulk of the electrode wire. An alternative approach involves creating a bore in the wall of the foam tip that the electrode can be threaded through. This method is hypothesized to reduce the likelihood of a slit leak before the electrode wire is integrated into the foam tip. The second objective of the study was to investigate how sound transmission in the ear is affected by placing an electrode on the eardrum. It was hypothesized that an electrode in contact with the eardrum increases the eardrum's mass, with the potential to reduce sound transmission at high frequencies. Wideband acoustic immittance and distortion product otoacoustic emissions (DPOAEs) were measured in eight human ears. Measurements were completed for five different conditions: (1) baseline with no electrode in the canal, (2) dry electrode in the canal but not touching the eardrum, secured underneath the eartip, (3) dry electrode in the canal not touching the eardrum, secured through a bore in the eartip (subsequent conditions were completed using this method), (4) hydrated electrode in the canal but not touching the eardrum, and (5) hydrated electrode touching the eardrum. To create the bore, a technique was developed in which a needle is heated and pushed through the foam eartip. The electrode is then thread through the bore and advanced slowly by hand until contacting the eardrum. Analysis included comparing absorbance, admittance phase angle, and DPOAE levels between measurement conditions. Comparison of the absorbance and admittance phase angle measurements between the electrode placement methods revealed significantly higher absorbance and lower admittance phase angle from 0.125 to 1 kHz when the electrode is routed under the eartip. Absorbance and admittance phase angle were minimally affected when the electrode was inserted through a bore in the eartip. DPOAE levels across the different conditions showed changes approximating test-retest variability. Upon contacting the eardrum, the absorbance tended to decrease below 1 kHz and increase above 1 kHz. However, changes were within the range of test-retest variability. There was evidence of reduced levels below 1 kHz and increased levels above 1 kHz upon the electrode contacting the eardrum. However, differences between conditions approximated test-retest variability. Routing the eardrum electrode through the foam tip reduces the likelihood of incurring an acoustic leak between the canal walls and eartip, compared with routing the electrode under the eartip. Changes in absorbance and DPOAE levels resulting from electrode contact with the eardrum implicate potential stiffening of eardrum; however, the magnitude of changes suggests minimal effect of the electrode on sound transmission in the ear.