Patient-tailored risk assessment of obstructive coronary artery disease using Rubidium-82 PET-based myocardial flow quantification with visual interpretation.

INTRODUCTION: Our aim was to estimate the probability of obstructive CAD (oCAD) for an individual patient as a function of the myocardial flow reserve (MFR) measured with Rubidium-82 (Rb-82) PET in patients with a visually normal or abnormal scan. MATERIALS AND METHODS: We included 1519 consecutive patients without a prior history of CAD referred for rest-stress Rb-82 PET/CT. All images were visually assessed by two experts and classified as normal or abnormal. We estimated the probability of oCAD for visually normal scans and scans with small (5%-10%) or larger defects (> 10%) as function of MFR. The primary endpoint was oCAD on invasive coronary angiography, when available. RESULTS: 1259 scans were classified as normal, 136 with a small defect and 136 with a larger defect. For the normal scans, the probability of oCAD increased exponentially from 1% to 10% when segmental MFR decreased from 2.1 to 1.3. For scans with small defects, the probability increased from 13% to 40% and for larger defects from 45% to > 70% when segmental MFR decreased from 2.1 to 0.7. CONCLUSION: Patients with > 10% risk of oCAD can be distinguished from patients with < 10% risk based on visual PET interpretation only. However, there is a strong dependence of MFR on patient's individual risk of oCAD. Hence, combining both visual interpretation and MFR results in a better individual risk assessment which may impact treatment strategy.

Machine learning based model to diagnose obstructive coronary artery disease using calcium scoring, PET imaging, and clinical data.

INTRODUCTION: Accurate risk stratification in patients with suspected stable coronary artery disease is essential for choosing an appropriate treatment strategy. Our aim was to develop and validate a machine learning (ML) based model to diagnose obstructive CAD (oCAD). METHOD: We retrospectively have included 1007 patients without a prior history of CAD who underwent CT-based calcium scoring (CACS) and a Rubidium-82 PET scan. The entire dataset was split 4:1 into a training and test dataset. An ML model was developed on the training set using fivefold stratified cross-validation. The test dataset was used to compare the performance of expert readers to the model. The primary endpoint was oCAD on invasive coronary angiography (ICA). RESULTS: ROC curve analysis showed an AUC of 0.92 (95% CI 0.90-0.94) for the training dataset and 0.89 (95% CI 0.84-0.93) for the test dataset. The ML model showed no significant differences as compared to the expert readers (p ≥ 0.03) in accuracy (89% vs. 88%), sensitivity (68% vs. 69%), and specificity (92% vs. 90%). CONCLUSION: The ML model resulted in a similar diagnostic performance as compared to expert readers, and may be deployed as a risk stratification tool for obstructive CAD. This study showed that utilization of ML is promising in the diagnosis of obstructive CAD.

The course of post-stroke apathy in relation to cognitive functioning: a prospective longitudinal cohort study.

Apathy is common after stroke and has been associated with cognitive impairment. However, causality between post-stroke apathy and cognitive impairment remains unclear. We assessed the course of apathy in relation to changes in cognitive functioning in stroke survivors. Using the Apathy Scale (AS) and cognitive tests on memory, processing speed and executive functioning at six- and 15 months post-stroke we tested for associations between (1) AS-scores and (change in) cognitive scores; (2) apathy course (persistent/incident/resolved) and cognitive change scores. Of 117 included participants, 29% had persistent apathy, 13% apathy resolving over time and 10% apathy emerging between 6-15 months post-stroke. Higher AS-scores were cross-sectionally and longitudinally associated with lower cognitive scores. Relations between apathy and cognitive change scores were ambiguous. These inconsistent relations between apathy and changes in cognition over time suggest that post-stroke apathy does not directly impact cognitive performance. Both these sequelae of stroke require separate attention.

Cerebral perfusion and the risk of cognitive decline and dementia in community dwelling older people.

Background: The arterial spin labeling-spatial coefficient of variation (sCoV) is a new vascular magnetic resonance imaging (MRI) parameter that could be a more sensitive marker for dementia-associated cerebral microvascular disease than the commonly used MRI markers cerebral blood flow (CBF) and white matter hyperintensity volume (WMHV). Methods: 195 community-dwelling older people with hypertension were invited to undergo MRI twice, with a three-year interval. Cognition was evaluated every two years for 6-8 years using the mini-mental state examination (MMSE). We assessed relations of sCoV, CBF and WMHV with cognitive decline during follow-up. We also registered dementia diagnoses, up to 9 years after the first scan. In an additional analysis, we compared these MRI parameters between participants that did and did not develop dementia. Results: 136/195 completed the second scan. sCoV and CBF were not associated with MMSE changes during 6-8 years of follow-up. Higher WMHV was associated with declining MMSE scores (-0.02 points/year/ml, 95%CI=-0.03 to -0.00). ScOv and CBF did not differ between participants who did (n=15) and did not (n=180) develop dementia, whereas higher WMHV was reported in participants who developed dementia after the first MRI (13.3 vs 6.1mL, p<0.001). There were no associations between longitudinal change in any of the MRI parameters and cognitive decline or subsequent dementia. Conclusion: Global sCoV and CBF were less sensitive longitudinal markers of cognitive decline and dementia compared to WMHV in community-dwelling older people with hypertension. Larger longitudinal MRI perfusion studies are needed to identify possible (regional) patterns of cerebral perfusion preceding cognitive decline and dementia diagnosis.

The Effect of Multidomain Interventions on Global Cognition, Symptoms of Depression and Apathy - A Pooled Analysis of Two Randomized Controlled Trials.

BACKGROUND: Cardiovascular risk factors and lifestyle factors are associated with an increased risk of cognitive decline and dementia in observational studies, and have been targeted by multidomain interventions. OBJECTIVES: We pooled individual participant data from two multi-domain intervention trials on cognitive function and symptoms of depression to increase power and facilitate subgroup analyses. DESIGN: Pooled analysis of individual participant data. SETTING: Prevention of Dementia by Intensive Vascular Care trial (preDIVA) and Multidomain Alzheimer Preventive Trial (MAPT). PARTICIPANTS: Community-dwelling individuals, free from dementia at baseline. INTERVENTION: Multidomain interventions focused on cardiovascular and lifestyle related risk factors. MEASUREMENTS: Data on cognitive functioning, depressive symptoms and apathy were collected at baseline, 2 years and 3-4 years of follow-up as available per study. We analyzed crude scores with linear mixed models for overall cognitive function (Mini Mental State Examination [MMSE]), and symptoms of depression and apathy (15-item Geriatric Depression Scale). Prespecified subgroup analyses were performed for sex, educational level, baseline MMSE <26, history of hypertension, and history of stroke, myocardial infarction and/or diabetes mellitus. RESULTS: We included 4162 individuals (median age 74 years, IQR 72, 76) with a median follow-up duration of 3.7 years (IQR 3.0 to 4.1 years). No differences between intervention and control groups were observed on change in cognitive functioning scores and symptoms of depression and apathy scores in the pooled study population. The MMSE declined less in the intervention groups in those with MMSE <26 at baseline (N=250; MD: 0.84; 95%CI: 0.15 to 1.54; p<0.001). CONCLUSIONS: We found no conclusive evidence that multidomain interventions reduce the risk of global cognitive decline, symptoms of depression or apathy in a mixed older population. Our results suggest that these interventions may be more effective in those with lower baseline cognitive functioning. Extended follow-up for dementia occurrence is important to inform on the potential long-term effects of multidomain interventions.

Semi-quantitative assessment of ischemia with rubidium-82 PET myocardial perfusion imaging.

PURPOSE: Semi-quantitative scores can be used as an adjunct to visual assessment in rubidium-82 positron emission tomography (82Rb PET). The semi-quantitative cut-off values used in 82Rb PET are derived from single-photon emission computed tomography (SPECT). It is unknown whether these cut-off values can be extrapolated to 82Rb PET. We compared the semi-quantitative with the visual assessment of ischemia and determined which summed difference score (SDS) score predicts ischemia best. METHODS: We included 108 patients who underwent 82Rb PET imaging and performed visual and semi-quantitative assessment. A scan with a SDS ≥ 2 and a summed stress score (SSS) ≥ 4 was considered to demonstrate ischemia. We compared the semi-quantitative with the visual assessment. RESULTS: 41 (38%) Normal scans, and 67 (62%) scans with ischemia and/or an irreversible defect were included. The semi-quantitative assessment showed ischemia more often than the visual assessment (51% vs 29%, P < .001). Patients with a low or intermediate pre-test probability of coronary artery disease (CAD) and a SDS < 4 did not demonstrate ischemia by visual assessment. CONCLUSION: Semi-quantitative assessment in 82Rb PET imaging clearly demonstrates the presence of ischemia. Ischemia is unlikely in patients with low and intermediate pre-test probability of CAD and a SDS < 4.

Value of SiPM PET in myocardial perfusion imaging using Rubidium-82.

BACKGROUND: PET scanners using silicon photomultipliers with digital readout (SiPM PET) have an improved temporal and spatial resolution compared to PET scanners using conventional photomultiplier tubes (PMT PET). However, the effect on image quality and visibility of perfusion defects in myocardial perfusion imaging (MPI) is unknown. Our aim was to determine the value of a SiPM PET scanner in MPI. METHODS: We prospectively included 30 patients who underwent rest and regadenoson-induced stress Rubidium-82 (Rb-82) MPI on the D690 PMT PET (GE Healthcare) and within three weeks on the Vereos SiPM PET (Philips Healthcare). Two expert readers scored the image quality and assessed the existence of possible defects. In addition, interpreter's confidence, myocardial blood flow (MBF), and myocardial flow reserve (MFR) values were compared. RESULTS: Image quality improved (P = 0.03) using the Vereos as compared to the D690. Image quality of the Vereos and the D690 was graded fair in 20% and 10%, good in 60% and 50%, and excellent in 20% and 40%, respectively. Defect interpretation and interpreter's confidence did not differ between the D690 and the Vereos (P > 0.50). There were no significant differences in rest MBF (P ≥ 0.29), stress MBF (P ≥ 0.11), and MFR (P ≥ 0.51). CONCLUSION: SiPM PET provides an improved image quality in comparison with PMT PET. Defect interpretation, interpreter's confidence, and absolute blood flow measurements were comparable between both systems. SiPM PET is therefore a reliable technique for MPI using Rb-82. TRIAL REGISTRATION: ToetsingOnline NL63853.075.17. Registered 13 November, 2017.

Effect of temporal sampling protocols on myocardial blood flow measurements using Rubidium-82 PET.

BACKGROUND: A variety of temporal sampling protocols is used worldwide to measure myocardial blood flow (MBF). Both the length and number of time frames in these protocols may alter MBF and myocardial flow reserve (MFR) measurements. We aimed to assess the effect of different clinically used temporal sampling protocols on MBF and MFR quantification in Rubidium-82 (Rb-82) PET imaging. METHODS: We retrospectively included 20 patients referred for myocardial perfusion imaging using Rb-82 PET. A literature search was performed to identify appropriate sampling protocols. PET data were reconstructed using 14 selected temporal sampling protocols with time frames of 5-10 seconds in the first-pass phase and 30-120 seconds in the tissue phase. Rest and stress MBF and MFR were calculated for all protocols and compared to the reference protocol with 26 time frames. RESULTS: MBF measurements differed (P ≤ 0.003) in six (43%) protocols in comparison to the reference protocol, with mean absolute relative differences up to 16% (range 5%-31%). Statistically significant differences were most frequently found for protocols with tissue phase time frames < 90 seconds. MFR did not differ (P ≥ 0.11) for any of the protocols. CONCLUSIONS: Various temporal sampling protocols result in different MBF values using Rb-82 PET. MFR measurements were more robust to different temporal sampling protocols.

Added value of coronary artery calcium score in the reporting of SPECT versus PET myocardial perfusion imaging.

BACKGROUND: Knowledge of coronary artery calcium score (CACS) influences the interpretation of myocardial perfusion imaging (MPI) with SPECT; however, the impact on PET interpretation remains unclear. We compared the added value of CACS to reporting MPI using SPECT vs PET. METHODS: We retrospectively included 412 patients. 206 patients who underwent Rb-82 PET were propensity-based matched to a cohort of 4018 patients who underwent cadmium-zinc-telluride SPECT MPI to obtain a comparable group of 206 SPECT patients. Next, we created four image sets: SPECT MPI-only, PET-only, SPECT + CACS, and PET + CACS. Two physicians interpreted the 824 images as normal, equivocal, or abnormal for ischemia or irreversible defects. Additionally, event rates were compared between PET and SPECT groups during 30-month follow-up. RESULTS: PET yielded more scans interpreted as normal than SPECT (88% vs 80%, respectively, P = 0.015). Adding CACS to SPECT increased the percentage of normal scans to 86% (P = 0.014), whereas this effect was absent for PET (90%, P = 0.77). Annualized event rates for images interpreted as normal did not differ and varied between 0.7 and 2.0% (P > 0.084). CONCLUSION: Adding CACS correctly increased the percentage of normal scans for SPECT MPI but not for PET, possibly limiting the effect of adding CACS to reporting PET.

Clinical value of machine learning-based interpretation of I-123 FP-CIT scans to detect Parkinson's disease: a two-center study.

PURPOSE: Our aim was to develop and validate a machine learning (ML)-based approach for interpretation of I-123 FP-CIT SPECT scans to discriminate Parkinson's disease (PD) from non-PD and to determine its generalizability and clinical value in two centers. METHODS: We retrospectively included 210 consecutive patients who underwent I-123 FP-CIT SPECT imaging and had a clinically confirmed diagnosis. Linear support vector machine (SVM) was used to build a classification model to discriminate PD from non-PD based on I-123-FP-CIT striatal uptake ratios, age and gender of 90 patients. The model was validated on unseen data from the same center where the model was developed (n = 40) and consecutively on data from a different center (n = 80). Prediction performance was assessed and compared to the scan interpretation by expert physicians. RESULTS: Testing the derived SVM model on the unseen dataset (n = 40) from the same center resulted in an accuracy of 95.0%, sensitivity of 96.0% and specificity of 93.3%. This was identical to the classification accuracy of nuclear medicine physicians. The model was generalizable towards the other center as prediction performance did not differ thereby obtaining an accuracy of 82.5%, sensitivity of 88.5% and specificity of 71.4% (p = NS). This was comparable to that of nuclear medicine physicians (p = NS). CONCLUSION: ML-based interpretation of I-123-FP-CIT scans results in accurate discrimination of PD from non-PD similar to visual assessment in both centers. The derived SVM model is therefore generalizable towards centers using comparable acquisition and image processing methods and implementation as diagnostic aid in clinical practice is encouraged.

Body weight-dependent Rubidium-82 activity results in constant image quality in myocardial perfusion imaging with PET.

BACKGROUND: Clinical practice shows degrading image quality in heavier patients who undergo myocardial perfusion imaging (MPI) with Rubidium-82 (Rb-82) PET when using a fixed tracer activity. Our aim was to derive and validate a patient-specific activity protocol resulting in a constant image quality in PET MPI. METHODS: We included 251 patients who underwent rest MPI with Rb-82 PET (Discovery 670, GE Healthcare). 132 patients were included retrospectively and were scanned using a fixed activity of 740 MBq. The total number of measured prompts was normalized to activity and correlated to body weight, mass per body length and body mass index to find the best predicting parameter. Next, a patient-specific activity was derived and subsequently validated in 119 additional patients. Image quality was scored by three experts on a four-point scale. RESULTS: Both image quality and prompts decreased in heavier patients when using a fixed activity (p < .005). Body weight was used to derive a new activity formula: Activity = 8.3 MBq/kg. When applying this formula, both measured prompts and scored image quality became independent of body weight (p > .60). CONCLUSION: Administrating a Rb-82 activity that linearly depends on body weight resulted in a constant image quality across all patients and is recommended.

Predictive value of traditional risk factors for cardiovascular disease in older people: A systematic review.

With increasing age, associations between traditional risk factors (TRFs) and cardiovascular disease (CVD) shift. It is unknown which mid-life risk factors remain relevant predictors for CVD in older people. We systematically searched PubMed and EMBASE on August 16th 2019 for studies assessing predictive ability of >1 of fourteen TRFs for fatal and non-fatal CVD, in the general population aged 60+. We included 12 studies, comprising 11 unique cohorts. TRF were evaluated in 2 to 11 cohorts, and retained in 0-70% of the cohorts: age (70%), diabetes (64%), male sex (57%), systolic blood pressure (SBP) (50%), smoking (36%), high-density lipoprotein cholesterol (HDL) (33%), left ventricular hypertrophy (LVH) (33%), total cholesterol (22%), diastolic blood pressure (20%), antihypertensive medication use (AHM) (20%), body mass index (BMI) (0%), hypertension (0%), low-density lipoprotein cholesterol (0%). In studies with low to moderate risk of bias, systolic blood pressure (SBP) (80%), smoking (80%) and HDL cholesterol (60%) were more often retained. Model performance was moderate with C-statistics ranging from 0.61 to 0.77. Compared to middle-aged adults, in people aged 60+ different risk factors predict CVD and current prediction models perform only moderate at best. According to most studies, age, sex and diabetes seem valuable predictors of CVD in old-age. SBP, HDL cholesterol and smoking may also have predictive value. Other blood pressure and cholesterol related variables, BMI, and LVH seem of very limited or no additional value. Without competing risk analysis, predictors are overestimated.

Correction to: No need for frame-wise attenuation correction in dynamic Rubidium-82 PET for myocardial blood flow quantification.

Due to the typesetter not carrying out the author's corrections at proof stage, there are two errors in the published article: where "mL × min × g" appears, it should be "mL/min/g". One error is in the Figure 3 caption, and one error is in the second sentence under the heading "MBF Quantification". The original article has been corrected.

Impact of regadenoson-induced myocardial creep on dynamic Rubidium-82 PET myocardial blood flow quantification.

BACKGROUND: Repositioning of the heart during myocardial perfusion imaging (MPI) using Rubidium-82 (Rb-82) PET may occur when using regadenoson. Our aim was to determine the prevalence and the effect of correcting for this myocardial creep on myocardial blood flow (MBF) quantification. METHODS: We retrospectively included 119 consecutive patients who underwent dynamic rest- and regadenoson-induced stress MPI using Rb-82 PET. The presence of myocardial creep was visually assessed in the dynamic stress PET series by identifying differences between the automatically drawn myocardium contour and the activity. Uncorrected and corrected stress MBFs were compared for the three vascular territories (LAD, LCX, and RCA) and for the whole myocardium. RESULTS: Myocardial creep was observed in 52% of the patients during stress. Mean MBF values decreased after correction in the RCA from 4.0 to 2.7 mL/min/g (P  < 0.001), in the whole myocardium from 2.7 to 2.6 mL/min/g (P  = 0.01), and increased in the LAD from 2.5 to 2.6 mL/min/g (P  = 0.03) and remained comparable in the LCX (P  = 0.3). CONCLUSIONS: Myocardial creep is a frequent phenomenon when performing regadenoson-induced stress Rb-82 PET and has a significant impact on MBF values, especially in the RCA territory. As this may hamper diagnostic accuracy, myocardial creep correction seems necessary for reliable quantification.

How to detect and correct myocardial creep in myocardial perfusion imaging using Rubidium-82 PET?

Reliability of myocardial blood flow (MBF) quantification in myocardial perfusion imaging (MPI) using PET can majorly be affected by the occurrence of myocardial creep when using pharmacologically induced stress. In this paper, we provide instructions on how to detect and correct for myocardial creep. For example, in each time frame of the PET images the myocardium contour and the observed activity have to be compared to check for misalignments. In addition, we provide an overview of the functionality of commonly used software packages to perform this quality control step as not all software packages currently provide this functionality. Furthermore, important clinical considerations to obtain accurate MBF measurements are given.

No need for frame-wise attenuation correction in dynamic Rubidium-82 PET for myocardial blood flow quantification.

BACKGROUND: Regadenoson-induced stress causes a repositioning of the heart, myocardial creep, in half of the patients undergoing Rubidium-82 (Rb-82) positron emission tomography (PET). As a result, misalignment of dynamic PET and computer tomography (CT) may occur, possibly affecting CT-based attenuation correction (AC) and thereby PET-based myocardial blood flow (MBF) quantification. Our aim was to determine the need for frame-wise PET-CT AC to obtain reliable MBF measurements. METHODS: 31 Out of 64 consecutive patients had myocardial creep during regadenoson-induced stress Rb-82 PET-CT and were included. Prior to PET image reconstruction, we applied two AC methods; single PET-CT alignment and frame-wise alignment in which PET time-frames with myocardial creep were individually co-registered with CT. The PET-CT misalignment was then quantified and MBFs for the three vascular territories and whole myocardium were calculated and compared between both methods. RESULTS: The magnitude of misalignment due to myocardial creep was 13.8 ± 4.5 mm in caudal-cranial direction, 1.8 ± 2.1 mm in medial-lateral and 2.5 ± 1.8 mm in anterior-posterior direction. Frame-wise PET-CT registration did not result in different MBF measurements (P ≥ .07) and the magnitude of misalignment and MBF differences did not correlate (P ≥ .58). CONCLUSION: There is no need for frame-wise AC in dynamic Rb-82 PET for MBF quantification. Single alignment seems sufficient in patients with myocardial creep.

Minimal rest activity for SPECT myocardial perfusion imaging in a one-day stress-first protocol.

PURPOSE: Guidelines propose different rest-stress activity ratios (RSAR) for one-day stress-first SPECT myocardial perfusion imaging (MPI), but evidence is limited. Our aim was to determine and validate the minimal RSAR resulting in the same diagnostic outcome in one-day stress-first SPECT MPI. METHODS: Forty-seven patients referred for rest after stress CZT-SPECT/CT MPI were prospectively included. Rest acquisitions were performed 3 h after stress. In addition to the stress and rest acquisitions, the first 22 patients underwent an additional acquisition prior to the rest injection to determine the remaining stress activity. Next, we simulated six RSARs varying from 1.0 to 3.5 in both patients and a phantom and compared the images to those using the reference RSAR of 4.0. Differences in summed difference score (SDS) >2 or ischemic defect interpretation were considered to significantly influence diagnostic outcome. After deriving the minimal RSAR, it was validated in 25 additional patients by comparing it to a RSAR of 4.0. RESULTS: After 3 h only 26% of the stress activity was still present in the myocardium. SDS differences >2 were found in one (4%) patient using RSAR of 3.5, 2.5 and 2.0, in three (12%) using 1.5 and in five (20%) using SRAR of 1.0. These results were consistent with the phantom study showing SDS differences >2 for RSARs ≤1.5 and with the visual interpretation which showed an increased number of deviating scans for RSAR 1.0. Validating the RSAR of 2.0 resulted in a different SDS in one patient (SDS of 30 versus 11). Moreover, two scans were interpreted as ischemic instead of normal when using RSAR 2.0 and in two other scans the opposite was the case. CONCLUSIONS: A RSAR of 2.0 in one-day stress-first MPI SPECT seems sufficient to obtain accurate diagnostic outcomes and is therefore recommended to reduce radiation exposure.

Clinical validation of a pressure-standardized compression mammography system.

OBJECTIVES: Validation of a pressure-standardized compression mammography (PSCM) system, which aims to reduce discomfort and pain by applying the same pressure to every breast, independent of breast size. METHODS: We retrospectively studied mammograms of 39 patients acquired with a conventional force-standardized compression mammography (FSCM) technique and intra-individually compared them to mammograms acquired on a checkup visit with PSCM technique. Patients received one craniocaudal (CC) and one mediolateral oblique (MLO) compression for both breasts. All images were processed to obtain the contact area between the breast and the compression paddle. The pressure was calculated by dividing the compression force by the contact area. RESULTS: A total of 150 FSCM and 150 PSCM images were analyzed. The mean pressure decreased significantly from 17.1 to 12.8 kPa (p < 0.001), when using PSCM instead of FSCM. The applied pressure hardly depended on the breast contact area with the paddle (-0.014 kPa/cm2), while a clear dependency was observed using FSCM. Furthermore, the relative number of over-compressions reduced from 26% to 2%, benefitting patients with smaller breasts. CONCLUSIONS: Our study suggests that using PSCM can reduce patient discomfort and pain during mammographic compression compared to conventional FSCM as a result of lower average pressure. Moreover, standardized pressure may provide a more constant image quality, which could improve diagnostic performance.