Publications by authors named "Ian Law"

207 Publications

Evaluation of age at symptom onset, proband status, and sex as predictors of disease severity in pediatric catecholaminergic polymorphic ventricular tachycardia.

Heart Rhythm 2021 Jul 29. Epub 2021 Jul 29.

Amsterdam University Medical Center, Amsterdam, Netherlands; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart.

Background: Children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for sudden death, and a risk stratification tool does not exist.

Objective: The purpose of this study was to determine whether proband status, age at symptom onset, and/or sex are independent predictors of cardiac events.

Methods: A multicenter, ambispective, cohort of pediatric CPVT patients was categorized by sex, proband status, and age at symptom onset (D1: first decade of life [symptom onset <10 years] or D2: second decade of life [symptom onset 10-18 years, inclusive]). Demographics, therapy, genetics, and outcomes were compared between groups.

Results: A total of 133 patients were included and stratified into 58 D1 and 75 D2 patients (68 female and 65 male; 106 probands and 27 relatives). Localization of RYR2 variants to hotspots differed based on proband status and age at symptom onset. The cardiac event rate was 33% (n = 44/133), inclusive of a 3% (n = 4/133) mortality rate, over a median of 6 years (interquartile range 3-11) after time of symptom onset. Proband status, rather than age at of symptom onset or sex, was an independent predictor of time to first cardiac event (P = .008; hazard ratio = 4.4). The 5-, 10- and 15-year event-free survival rates for probands were 77%, 56%, and 46%, respectively, and for relatives were 96%, 91%, and 86%, respectively. Event risk after diagnosis was 48% (32/67) in patients on β-blocker or flecainide alone vs 10% (5/48) in patients on β-blocker plus flecainide and/or left cardiac sympathetic denervation (P <.001).

Conclusion: Proband status, but not age at symptom onset or male sex, independently predicted an earlier onset of cardiac events. A larger sample size would enable a comprehensive investigation of other risk factors.
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http://dx.doi.org/10.1016/j.hrthm.2021.07.061DOI Listing
July 2021

Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia.

Cerebellum 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.

Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.
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http://dx.doi.org/10.1007/s12311-021-01308-wDOI Listing
July 2021

Deep-learning-based attenuation correction in dynamic [O]HO studies using PET/MRI in healthy volunteers.

J Cereb Blood Flow Metab 2021 Jul 11:271678X211029178. Epub 2021 Jul 11.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Quantitative [O]HO positron emission tomography (PET) is the accepted reference method for regional cerebral blood flow (rCBF) quantification. To perform reliable quantitative [O]HO-PET studies in PET/MRI scanners, MRI-based attenuation-correction (MRAC) is required. Our aim was to compare two MRAC methods (RESOLUTE and DeepUTE) based on ultrashort echo-time with computed tomography-based reference standard AC (CTAC) in dynamic and static [O]HO-PET. We compared rCBF from quantitative perfusion maps and activity concentration distribution from static images between AC methods in 25 resting [O]HO-PET scans from 14 healthy men at whole-brain, regions of interest and voxel-wise levels. Average whole-brain CBF was 39.9 ± 6.0, 39.0 ± 5.8 and 40.0 ± 5.6 ml/100 g/min for CTAC, RESOLUTE and DeepUTE corrected studies respectively. RESOLUTE underestimated whole-brain CBF by 2.1 ± 1.50% and rCBF in all regions of interest (range -2.4%- -1%) compared to CTAC. DeepUTE showed significant rCBF overestimation only in the occipital lobe (0.6 ± 1.1%). Both MRAC methods showed excellent correlation on rCBF and activity concentration with CTAC, with slopes of linear regression lines between 0.97 and 1.01 and R over 0.99. In conclusion, RESOLUTE and DeepUTE provide AC information comparable to CTAC in dynamic [O]HO-PET but RESOLUTE is associated with a small but systematic underestimation.
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http://dx.doi.org/10.1177/0271678X211029178DOI Listing
July 2021

Hybrid 2-[18F] FDG PET/MRI in premanifest Huntington's disease gene-expansion carriers: The significance of partial volume correction.

PLoS One 2021 11;16(6):e0252683. Epub 2021 Jun 11.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Huntington's disease (HD) is an inherited, progressive neurodegenerative disease that has no cure. Striatal atrophy and hypometabolism has been described in HD as far as 15 years before clinical onset and therefore structural and functional imaging biomarkers are the most applied biomarker modalities which call for these to be exact; however, most studies are not considering the partial volume effect and thereby tend to overestimate metabolic reductions, which may bias imaging outcome measures of interventions.

Objective: Evaluation of partial volume effects in a cohort of premanifest HD gene-expansion carriers (HDGECs).

Methods: 21 HDGECs and 17 controls had a hybrid 2-[18F]FDG PET/MRI scan performed. Volume measurements and striatal metabolism, both corrected and uncorrected for partial volume effect were correlated to an estimate of disease burden, the CAG age product scaled (CAPS).

Results: We found significantly reduced striatal metabolism in HDGECs, but not in striatal volume. There was a negative correlation between the CAPS and striatal metabolism, both corrected and uncorrected for the partial volume effect. The partial volume effect was largest in the smallest structures and increased the difference in metabolism between the HDGEC with high and low CAPS scores. Statistical parametric mapping confirmed the results.

Conclusions: A hybrid 2-[18F]FDG PET/MRI scan provides simultaneous information on structure and metabolism. Using this approach for the first time on HDGECs, we highlight the importance of partial volume effect correction in order not to underestimate the standardized uptake value and thereby the risk of overestimating the metabolic effect on the striatal structures, which potentially could bias studies determining imaging outcome measures of interventions in HDGECs and probably also symptomatic HD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195345PMC
June 2021

Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry.

JAMA Cardiol 2021 09;6(9):1078-1087

Indiana University School of Medicine, Bloomington.

Importance: Myocarditis is a leading cause of sudden death in competitive athletes. Myocardial inflammation is known to occur with SARS-CoV-2. Different screening approaches for detection of myocarditis have been reported. The Big Ten Conference requires comprehensive cardiac testing including cardiac magnetic resonance (CMR) imaging for all athletes with COVID-19, allowing comparison of screening approaches.

Objective: To determine the prevalence of myocarditis in athletes with COVID-19 and compare screening strategies for safe return to play.

Design, Setting, And Participants: Big Ten COVID-19 Cardiac Registry principal investigators were surveyed for aggregate observational data from March 1, 2020, through December 15, 2020, on athletes with COVID-19. For athletes with myocarditis, presence of cardiac symptoms and details of cardiac testing were recorded. Myocarditis was categorized as clinical or subclinical based on the presence of cardiac symptoms and CMR findings. Subclinical myocarditis classified as probable or possible myocarditis based on other testing abnormalities. Myocarditis prevalence across universities was determined. The utility of different screening strategies was evaluated.

Exposures: SARS-CoV-2 by polymerase chain reaction testing.

Main Outcome And Measure: Myocarditis via cardiovascular diagnostic testing.

Results: Representing 13 universities, cardiovascular testing was performed in 1597 athletes (964 men [60.4%]). Thirty-seven (including 27 men) were diagnosed with COVID-19 myocarditis (overall 2.3%; range per program, 0%-7.6%); 9 had clinical myocarditis and 28 had subclinical myocarditis. If cardiac testing was based on cardiac symptoms alone, only 5 athletes would have been detected (detected prevalence, 0.31%). Cardiac magnetic resonance imaging for all athletes yielded a 7.4-fold increase in detection of myocarditis (clinical and subclinical). Follow-up CMR imaging performed in 27 (73.0%) demonstrated resolution of T2 elevation in all (100%) and late gadolinium enhancement in 11 (40.7%).

Conclusions And Relevance: In this cohort study of 1597 US competitive athletes with CMR screening after COVID-19 infection, 37 athletes (2.3%) were diagnosed with clinical and subclinical myocarditis. Variability was observed in prevalence across universities, and testing protocols were closely tied to the detection of myocarditis. Variable ascertainment and unknown implications of CMR findings underscore the need for standardized timing and interpretation of cardiac testing. These unique CMR imaging data provide a more complete understanding of the prevalence of clinical and subclinical myocarditis in college athletes after COVID-19 infection. The role of CMR in routine screening for athletes safe return to play should be explored further.
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http://dx.doi.org/10.1001/jamacardio.2021.2065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160916PMC
September 2021

Finding our way through the labyrinth of dementia biomarkers.

Eur J Nucl Med Mol Imaging 2021 07;48(8):2320-2324

Department of Nuclear Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.1007/s00259-021-05301-7DOI Listing
July 2021

Diagnostic Accuracy and Clinical Impact of [ 18F]FET PET in Childhood CNS tumors.

Neuro Oncol 2021 Apr 17. Epub 2021 Apr 17.

Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet, Denmark.

Background: Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[ 18F]fluoroethyl)-L-tyrosine ([ 18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [ 18F]FET PET to MRI in children with CNS tumors.

Methods: A total of 169 [ 18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse.

Results: Adding [ 18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4-13%] of all scans (n=151) and in 33% [CI: 17-53%] of scans deemed clinically indicated due to difficult decision-making on MRI alone (n=30). Using pathology or follow-up as reference standard, the addition of [ 18F]FET PET increased specificity (1.00 [0.82-1.00] vs. 0.48 [0.30-0.70], p=0.0001) and accuracy (0.91 [CI: 0.87-0.96] vs. 0.81 [CI: 0.75-0.89], p=0.04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI:0.91-1.00] vs 0.90 [CI:0.82-0.92], p<0.001). Further, in a subset of patients (n=15) [ 18F]FET uptake correlated positively with genomic proliferation index.

Conclusions: The addition of [ 18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date.
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http://dx.doi.org/10.1093/neuonc/noab096DOI Listing
April 2021

Regional and interindividual relationships between cerebral perfusion and oxygen metabolism.

J Appl Physiol (1985) 2021 06 8;130(6):1836-1847. Epub 2021 Apr 8.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark.

Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO) show large between-subject and regional variability, but the relationships between CBF and CMRO measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO measures with independent and quantitative PET techniques. We included resting CBF and CMRO measurements from 50 healthy volunteers (aged 22-81 yr), and calculated the regional and global values of oxygen delivery (Do) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial Pco and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between Do and CMRO, resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by Pco and hemoglobin concentration. Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO, but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual measures of oxygen metabolism. The analysis further showed smaller, but significant regional differences of oxygen extraction fraction at rest.
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http://dx.doi.org/10.1152/japplphysiol.00939.2020DOI Listing
June 2021

PET Imaging in Neurodegeneration and Neuro-oncology: Variants and Pitfalls.

Semin Nucl Med 2021 Sep 3;51(5):408-418. Epub 2021 Apr 3.

Department of Nuclear Medicine, University Hospital Leuven, Division of Nuclear Medicine and Molecular Imaging, KU Leuven, Leuven, Belgium. Electronic address:

In neurodegenerative diseases, positron emission tomography (PET) imaging plays an important role in the early identification and differential diagnosis in particular in clinically challenging patients. F-FDG is still the most widely used and established tracer in this patient group, with different cortical and subcortical regions being preferentially affected in different neurodegenerative diseases, such as frontotemporal dementia, Alzheimer's disease or Lewy Body dementia, resulting in typical hypometabolic patterns. Over the last decades, however, the implementation of tracers specific for the pathological deposits characteristic of the different diseases, such as amyloid and tau, has revolutionized the way of classifying and reporting cases of cognitive impairment of neurodegenerative origin, providing complementary information to F-FDG PET. In neuro-oncology, PET imaging can be performed in several clinical indications, as highlighted in the joint European Association of Nuclear Medicine (EANM)/European Association of Neuro-Oncology (EANO)/Response assessment in neuro-oncology (RANO) practice guidelines on imaging in neuro-oncology. For assessment of glioma, amino-acid analogues, such as C-methionine or F-FET, are used whenever clinically available, as they offer excellent tumor-to-background ratios in malignant tumors. Moreover, dynamic acquisition of amino-acid analogue tracers and assessment of the shape of the time-activity curve can be used to perform noninvasive grading of brain gliomas, differentiating low from high grade presentations. In both settings, however, thorough knowledge of the normal physiological tracer distribution and the variants and pitfalls that can occur during image acquisition, processing and interpretation is mandatory in order to provide optimal diagnostic information to referring physicians and patients. Especially in neuro-oncology, this process can be aided by the active use of coregistered magnetic resonance imaging to accurately identify the imaging correlates of developmental origin, acute and chronic stroke, inflammation, infection and seizure related activity.
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http://dx.doi.org/10.1053/j.semnuclmed.2021.03.003DOI Listing
September 2021

Validation of kinetic modeling of [O]HO PET using an image derived input function on hybrid PET/MRI.

Neuroimage 2021 06 11;233:117950. Epub 2021 Mar 11.

Department of Clinical Physiology, Nuclear Medicine, and PET, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.

In present study we aimed to validate the use of image-derived input functions (IDIF) in the kinetic modeling of cerebral blood flow (CBF) measured by [O]HO PET by comparing with the accepted reference standard arterial input function (AIF). Additional comparisons were made to mean cohort AIF and CBF values acquired by methodologically independent phase-contrast mapping (PCM) MRI. Using hybrid PET/MRI an IDIF was generated by measuring the radiotracer concentration in the internal carotid arteries and correcting for partial volume effects using the intravascular volume measured from MRI-angiograms. Seven patients with carotid steno-occlusive disease and twelve healthy controls were examined at rest, after administration of acetazolamide, and, in the control group, during hyperventilation. Agreement between the techniques was examined by linear regression and Bland-Altman analysis. Global CBF values modeled using IDIF correlated with values from AIF across perfusion states in both patients (p<10, R=0.82, 95% limits of agreement (LoA)=[-11.3-9.9] ml/100 g/min) and controls (p<10, R=0.87, 95% LoA=[-17.1-13.7] ml/100 g/min). The reproducibility of gCBF using IDIF was identical to AIF (15.8%). Values from IDIF and AIF had equally good correlation to measurements by PCM MRI, R=0.86 and R=0.84, (p<10), respectively. Mean cohort AIF performed substantially worse than individual IDIFs (p<10, R=0.63, LoA=[-12.8-25.3] ml/100 g/min). In the patient group, use of IDIF provided similar reactivity maps compared to AIF. In conclusion, global CBF values modeled using IDIF correlated with values modeled by AIF and similar perfusion deficits could be established in a patient group.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117950DOI Listing
June 2021

Comparison of the clinical impact of 2-[18F]FDG-PET and cerebrospinal fluid biomarkers in patients suspected of Alzheimer's disease.

PLoS One 2021 12;16(3):e0248413. Epub 2021 Mar 12.

Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: The two biomarkers 2-[18F]FDG-PET and cerebrospinal fluid biomarkers are both recommended to support the diagnosis of Alzheimer's disease. However, there is a lack of knowledge for the comparison of the two biomarkers in a routine clinical setting.

Objective: The aim was to compare the clinical impact of 2-[18F]FDG-PET and cerebrospinal fluid biomarkers on diagnosis, prognosis, and patient management in patients suspected of Alzheimer's disease.

Methods: Eighty-one patients clinically suspected of Alzheimer's disease were retrospectively included from the Copenhagen Memory Clinic. As part of the clinical work-up all patients had a standard diagnostic program examination including MRI and ancillary investigations with 2-[18F]FDG-PET and cerebrospinal fluid biomarkers. An incremental study design was used to evaluate the clinical impact of the biomarkers. First, the diagnostic evaluation was based on the standard diagnostic program, then the diagnostic evaluation was revised after addition of either cerebrospinal fluid biomarkers or 2-[18F]FDG-PET. At each diagnostic evaluation, two blinded dementia specialists made a consensus decision on diagnosis, prediction of disease course, and change in patient management. Confidence in the decision was measured on a visual analogue scale (0-100). After 6 months, the diagnostic evaluation was performed with addition of the other biomarker. A clinical follow-up after 12 months was used as reference for diagnosis and disease course.

Results: The two biomarkers had a similar clinical value across all diagnosis when added individually to the standard diagnostic program. However, for the correctly diagnosed patient with Alzheimer's disease cerebrospinal fluid biomarkers had a significantly higher impact on diagnostic confidence (mean scores±SD: 88±11 vs. 82±11, p = 0.046) and a significant reduction in the need for ancillary investigations (23 vs. 18 patients, p = 0.049) compared to 2-[18F]FDG-PET.

Conclusion: The two biomarkers had similar clinical impact on diagnosis, but cerebrospinal fluid biomarkers had a more significant value in corroborating the diagnosis of Alzheimer's disease compared to 2-[18F]FDG-PET.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954298PMC
March 2021

Contribution of PET imaging to radiotherapy planning and monitoring in glioma patients - a report of the PET/RANO group.

Neuro Oncol 2021 06;23(6):881-893

German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.

The management of patients with glioma usually requires multimodality treatment including surgery, radiotherapy, and systemic therapy. Accurate neuroimaging plays a central role for radiotherapy planning and follow-up after radiotherapy completion. In order to maximize the radiation dose to the tumor and to minimize toxic effects on the surrounding brain parenchyma, reliable identification of tumor extent and target volume delineation is crucial. The use of positron emission tomography (PET) for radiotherapy planning and monitoring in gliomas has gained considerable interest over the last several years, but Class I data are not yet available. Furthermore, PET has been used after radiotherapy for response assessment and to distinguish tumor progression from pseudoprogression or radiation necrosis. Here, the Response Assessment in Neuro-Oncology (RANO) working group provides a summary of the literature and recommendations for the use of PET imaging for radiotherapy of patients with glioma based on published studies, constituting levels 1-3 evidence according to the Oxford Centre for Evidence-based Medicine.
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http://dx.doi.org/10.1093/neuonc/noab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168815PMC
June 2021

Improved Detection of Postoperative Residual Meningioma with [Ga]Ga-DOTA-TOC PET Imaging Using a High-resolution Research Tomograph PET Scanner.

Clin Cancer Res 2021 Apr 1;27(8):2216-2225. Epub 2021 Feb 1.

Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Denmark.

Purpose: PET with somatostatin receptor ligand [Ga]Ga-DOTA-D-Phe-Tyr-octreotide ([Ga]Ga-DOTA-TOC) is an established method in radiotherapy planning because of the improved detection and delineation of meningioma tissue. We investigated the diagnostic accuracy of supplementary [Ga]Ga-DOTA-TOC PET in patients with a 3-month postoperative MRI reporting gross-total resection (GTR).

Experimental Design: Thirty-seven patients with a histologically proven meningioma and GTR on postoperative MRI were prospectively referred to [Ga]Ga-DOTA-TOC PET. Detection and volume measurements of [Ga]Ga-DOTA-TOC-avid lesions in relation to the primary tumor site were recorded. Residual tumor in suspicious lesions suggested by [Ga]Ga-DOTA-TOC PET was verified by (i) tumor recurrence/progression on subsequent MRI scans according to the Response Assessment of Neuro-Oncology criteria, (ii) subsequent histology, and (iii) follow-up [Ga]Ga-DOTA-TOC PET scan.

Results: Twenty-three PET scans demonstrated [Ga]Ga-DOTA-TOC-avid lesions suspicious of residual meningioma, where 18 could be verified by (i) tumor progression on subsequent MRI scans ( = 6), (ii) histologic confirmation ( = 3), and (iii) follow-up [Ga]Ga-DOTA-TOC PET scans confirming the initial PET findings ( = 9) after an overall median follow-up time of 17 months (range, 9-35 months). In contrast, disease recurrence was seen in only 2 of 14 patients without [Ga]Ga-DOTA-TOC-avid lesions ( < 0.0001). The sensitivity, specificity, and diagnostic accuracy of [Ga]Ga-DOTA-TOC PET in detecting meningioma residue was 90% [95% confidence interval (CI), 67-99], 92% (95% CI, 62-100), and 90% (95% CI, 74-98; < 0.0001), respectively.

Conclusions: The majority of patients with GTR on 3-month postoperative MRI may have small unrecognized meningioma residues that can be detected using [Ga]Ga-DOTA-TOC PET.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3362DOI Listing
April 2021

PET imaging of meningioma with 18F-FLT: a predictor of tumour progression.

Brain 2020 12;143(11):3308-3317

Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet, Denmark.

We have previously reported that PET with 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) provides a non-invasive assessment of cell proliferation in vivo in meningiomas. The purpose of this prospective study was to evaluate the potential of 18F-FLT PET in predicting subsequent tumour progression in asymptomatic meningiomas. Forty-three adult patients harbouring 46 MRI-presumed (n = 40) and residual meningiomas from previous surgery (n = 6) underwent a 60-min dynamic 18F-FLT PET scan prior to radiological surveillance. Maximum and mean tumour-to-blood ratios (TBRmax, TBRmean) of tracer radioactivity were calculated. Tumour progression was defined according to the latest published trial end-point criteria for bidimensional (2D) and corresponding yet exploratory volumetric measurements from the Response Assessment of Neuro-Oncology (RANO) workgroup. Independent-sample t-test, Pearson correlation coefficient, Cox regression, and receiver operating characteristic (ROC) curve analyses were used whenever appropriate. The median follow-up time after 18F-FLT PET imaging was 18 months (range 5-33.5 months). A high concordance rate (91%) was found with regard to disease progression using 2D-RANO (n = 11) versus volumetric criteria (n = 10). Using 2D-RANO criteria, 18F-FLT uptake was significantly increased in patients with progressive disease, compared to patients with stable disease (TBRmax, 5.5 ± 1.3 versus 3.6 ± 1.1, P < 0.0001; TBRmean, 3.5 ± 0.8 versus 2.4 ± 0.7, P < 0.0001). ROC analysis yielded optimal thresholds of 4.4 for TBRmax [sensitivity 82%, specificity 77%, accuracy 78%, and area under curve (AUC) 0.871; P < 0.0001] and 2.8 for TBRmean (sensitivity 82%, specificity 77%, accuracy 78%, AUC 0.848; P = 0.001) for early differentiation of patients with progressive disease from patients with stable disease. Upon excluding patients with residual meningioma or patients with stable disease with less than 12 months follow-up, the thresholds remained unchanged with similar diagnostic accuracies. Moreover, positive correlations were found between absolute and relative tumour growth rates and 18F-FLT uptake (r < 0.513, P < 0.015) that remained similar when excluding patients with residual meningioma or patients with stable disease and shorter follow-up period. Diagnostic accuracies were slightly inferior at 76% when assessing disease progression using volumetric criteria, while the thresholds remained unchanged. Multivariate analysis revealed that TBRmax was the only independent predictor of tumour progression (P < 0.046), while age, gender, baseline tumour size, tumour location, peritumoural oedema, and residual meningioma had no influence. The study reveals that 18F-FLT PET is a promising surrogate imaging biomarker for predicting subsequent tumour progression in treatment-naïve and asymptomatic residual meningiomas.
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http://dx.doi.org/10.1093/brain/awaa267DOI Listing
December 2020

Prevalence of cognitive impairment and its relation to mental health in Danish lymphoma survivors.

Support Care Cancer 2021 Jun 28;29(6):3319-3328. Epub 2020 Oct 28.

Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, DK-2100, Copenhagen, Denmark.

Purpose: This study sought to investigate the prevalence of self-reported cognitive impairment and its relation to illness and treatment characteristics and mental health in Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL) survivors as cancer-related cognitive impairment has not been extensively studied in lymphoma survivors.

Methods: One hundred fifteen HL and DLBCL survivors (mean age = 40.3 years, mean months since completed treatment = 29.6) completed questionnaires on executive function and mental health. We examined the prevalence of executive impairment and compared illness and treatment characteristics and mental health across survivors reporting impaired and non-impaired executive functioning using chi-square, Cochran-Armitage, and Mann-Whitney U tests.

Results: We found that 39% reported executive impairment. Survivors reporting impaired executive functioning reported worse mental health (ps < .001) than survivors reporting non-impaired executive functioning. A larger proportion of the impaired group had received a high chemo dose compared to the non-impaired group although this result fell short of significance after adjustment for multiple comparisons (p = .017).

Conclusions: Self-reported cognitive impairment is prevalent in HL and DLBCL survivors and is associated with worse mental health and possibly high chemo dose. Future studies should investigate objective impairment and the possible dose-response relationship between chemo dose and cognitive impairment in lymphoma survivors.
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http://dx.doi.org/10.1007/s00520-020-05857-4DOI Listing
June 2021

Amyloid-PET and F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias.

Lancet Neurol 2020 11;19(11):951-962

Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at University College London, London, UK.

Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and F-fluorodeoxyglucose (F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.
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http://dx.doi.org/10.1016/S1474-4422(20)30314-8DOI Listing
November 2020

The Safety and Efficacy of Transcatheter Pulmonary Valve Replacement Combined with Electrophysiology Procedures.

Pediatr Cardiol 2021 Feb 13;42(2):289-293. Epub 2020 Oct 13.

Division of Pediatric Cardiology, University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA.

The objective of this study was to evaluate the safety and efficacy of combining transcatheter pulmonary valve replacement (TPVR) and electrophysiology (EP) procedures. A retrospective review was undertaken to identify TPVR and EP procedures that were concomitantly performed in the cardiac catheterization laboratory at University of Iowa Stead Family Children's Hospital from January 2011 to October 2019. Procedural and follow-up data were compared between patients who underwent TPVR and EP procedures in the same setting to those who received TPVR or EP procedure separately and that were similar in age and cardiac anatomy. A total of 8 patients underwent combined TPVR and EP procedures. One patient was excluded due to lack of adequate control, leaving seven study subjects (57% female; median age at time of procedure 16 years). The median follow-up time was 11.5 months (range 2-36 months). Patients who received combined TPVR and EP had shorter recovery times (combined: median 18.9 h; IQR 18.35-19.5 vs separate: median 27.98 h; IQR 21.42-39.25; p-value 0.031), shorter hospital length of stay (combined: median 27.5 h; IQR 26.47-31.4 vs separate: median 38.4 h; IQR 33.42-51.50; p-value 0.016), and a 51% reduction in total hospital charges (combined: median $171,640; IQR 135.43-219.22 vs separate: median $333,560 IQR 263.20-400.98; p-value 0.016). There were no significant differences in radiation dose or procedure time between the combined and control groups. The median radiation time for those who had the combination procedure was 30.5 min [IQR 29.6-47.9], and the median dose area product was 215 mGy [IQR 158-935]. In conclusion, combining TPVR and EP procedures is feasible, safe, and economically advantageous.
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http://dx.doi.org/10.1007/s00246-020-02481-1DOI Listing
February 2021

Flipping syncope: The case of an adolescent athlete with syncopal episodes ultimately diagnosed with catecholaminergic polymorphic ventricular tachycardia.

Clin Case Rep 2020 Aug 17;8(8):1409-1412. Epub 2020 May 17.

University of Iowa Carver College of Medicine Iowa City IA USA.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a channelopathy which can lead to fatal ventricular arrhythmias. The diagnosis can be challenging due to a wide variety of clinical presentations. In this case, we describe the unusual presentation and subsequent workup of a young patient who was ultimately diagnosed with CPVT.
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http://dx.doi.org/10.1002/ccr3.2854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455425PMC
August 2020

Somatostatin Receptor-Targeted Radiopeptide Therapy in Treatment-Refractory Meningioma: Individual Patient Data Meta-analysis.

J Nucl Med 2021 04 28;62(4):507-513. Epub 2020 Aug 28.

Department of Neurosurgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas. We performed an individual patient data meta-analysis, including all published data on meningioma patients treated with SSTR-targeted PRRT. The main outcomes were toxicity, response to treatment, progression-free survival (PFS), and overall survival (OS). We applied the Kaplan-Meier method to estimate survival probabilities and report incidence rates per 100 person-years. We applied Cox proportional hazards models to determine the effect of covariates. We screened 537 papers and identified 6 eligible cohort studies. We included a total of 111 patients who had treatment-refractory meningioma and received SSTR-targeted PRRT. Disease control was achieved in 63% of patients. The 6-mo PFS rates were 94%, 48%, and 0% for World Health Organization grades I, II, and III, respectively. The risk of disease progression decreased by 13% per 1,000-MBq increase in the total applied activity. The 1-y OS rates were 88%, 71%, and 52% for World Health Organization grades I, II, and III, respectively. The risk of death decreased by 17% per 1,000-MBq increase in the total applied activity. The main side effects comprised transient hematotoxicity, such as anemia in 22% of patients, leukopenia in 13%, lymphocytopenia in 24%, and thrombocytopenia in 17%. To our knowledge, this individual patient data meta-analysis represents the most comprehensive analysis of the benefits of and adverse events associated with SSTR-targeted PRRT for treatment-refractory meningioma. The treatment was well tolerated, achieved disease control in most cases, and showed promising results regarding PFS and OS.
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http://dx.doi.org/10.2967/jnumed.120.249607DOI Listing
April 2021

Effect of blood glucose and body weight on image quality in brain [18F]FDG PET imaging.

Nucl Med Commun 2020 Dec;41(12):1265-1274

Copenhagen University Hospital Rigshospitalet Copenhagen.

Objectives: The aims of the present study were to assess the influence of mild to moderate hyperglycaemia and body weight on brain 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG) PET, and to what extent a simple algorithm for maintaining count density may compensate for these effects.

Methods: We prospectively included 63 patients undergoing routine brain [F]FDG PET. Scan time and injected activity were adjusted in patients with hyperglycaemia or increased body weight. Measures of perceived image quality, image noise and image contrast were obtained in both standard scans and intervention scans.

Results: Elevated blood glucose and increased body weight were associated with reduced count density and increased image noise that in turn were associated with lower scores of perceived image quality. The proposed simple algorithm effectively maintained the image noise level and improved perceived image quality across the full range of elevated blood glucose values and body weights, although the effect of intervention on perceived image quality was attenuated by lower image contrast in patients with moderate hyperglycaemia. In patients with increased body weight or blood glucose, the fraction of scans with poor image quality decreased from 9/29 to 2/29 (P = 0.04) and the fraction with good image quality increased from 7/29 to 20/29 (P = 0.001) when applying the proposed algorithm.

Conclusions: Increasing blood glucose and body weight are associated with increased image noise in standard imaging conditions. Improving count density by prolonging scan time and increasing injected activity significantly improves image quality in hyperglycaemic patients, although the image contrast remains reduced in patients with most pronounced hyperglycaemia.
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http://dx.doi.org/10.1097/MNM.0000000000001281DOI Listing
December 2020

Mania triggered by levodopa treatment in a patient with frontotemporal dementia caused by A C9orf72 repeat expansion: A case report.

Clin Neurol Neurosurg 2020 11 8;198:106147. Epub 2020 Aug 8.

Department of Neurology, Rigshospitalet, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1016/j.clineuro.2020.106147DOI Listing
November 2020

AI-driven attenuation correction for brain PET/MRI: Clinical evaluation of a dementia cohort and importance of the training group size.

Neuroimage 2020 11 1;222:117221. Epub 2020 Aug 1.

Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, University of Copenhagen, Denmark.

Introduction: Robust and reliable attenuation correction (AC) is a prerequisite for accurate quantification of activity concentration. In combined PET/MRI, AC is challenged by the lack of bone signal in the MRI from which the AC maps has to be derived. Deep learning-based image-to-image translation networks present itself as an optimal solution for MRI-derived AC (MR-AC). High robustness and generalizability of these networks are expected to be achieved through large training cohorts. In this study, we implemented an MR-AC method based on deep learning, and investigated how training cohort size, transfer learning, and MR input affected robustness, and subsequently evaluated the method in a clinical setup, with the overall aim to explore if this method could be implemented in clinical routine for PET/MRI examinations.

Methods: A total cohort of 1037 adult subjects from the Siemens Biograph mMR with two different software versions (VB20P and VE11P) was used. The software upgrade included updates to all MRI sequences. The impact of training group size was investigated by training a convolutional neural network (CNN) on an increasing training group size from 10 to 403. The ability to adapt to changes in the input images between software versions were evaluated using transfer learning from a large cohort to a smaller cohort, by varying training group size from 5 to 91 subjects. The impact of MRI sequence was evaluated by training three networks based on the Dixon VIBE sequence (DeepDixon), T1-weighted MPRAGE (DeepT1), and ultra-short echo time (UTE) sequence (DeepUTE). Blinded clinical evaluation relative to the reference low-dose CT (CT-AC) was performed for DeepDixon in 104 independent 2-[F]fluoro-2-deoxy-d-glucose ([F]FDG) PET patient studies performed for suspected neurodegenerative disorder using statistical surface projections.

Results: Robustness increased with group size in the training data set: 100 subjects were required to reduce the number of outliers compared to a state-of-the-art segmentation-based method, and a cohort >400 subjects further increased robustness in terms of reduced variation and number of outliers. When using transfer learning to adapt to changes in the MRI input, as few as five subjects were sufficient to minimize outliers. Full robustness was achieved at 20 subjects. Comparable robust and accurate results were obtained using all three types of MRI input with a bias below 1% relative to CT-AC in any brain region. The clinical PET evaluation using DeepDixon showed no clinically relevant differences compared to CT-AC.

Conclusion: Deep learning based AC requires a large training cohort to achieve accurate and robust performance. Using transfer learning, only five subjects were needed to fine-tune the method to large changes to the input images. No clinically relevant differences were found compared to CT-AC, indicating that clinical implementation of our deep learning-based MR-AC method will be feasible across MRI system types using transfer learning and a limited number of subjects.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117221DOI Listing
November 2020

Prognostic value of complementary biomarkers of neurodegeneration in a mixed memory clinic cohort.

PeerJ 2020 9;8:e9498. Epub 2020 Jul 9.

Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Biomarkers of neurodegeneration, e.g. MRI brain atrophy and [F]FDG-PET hypometabolism, are often evaluated in patients suspected of neurodegenerative disease.

Objective: Our primary objective was to investigate prognostic properties of atrophy and hypometabolism.

Methods: From March 2015-June 2016, 149 patients referred to a university hospital memory clinic were included. The primary outcome was progression/stable disease course as assessed by a clinician at 12 months follow-up. Intracohort defined -scores of baseline MRI automatic quantified volume and [F]FDG-PET standardized uptake value ratios were calculated for all unilaterally defined brain lobes and dichotomized as pronounced atrophy (+A)/ pronounced hypometabolism (+H) at -score <0. A logistic regression model with progression status as the outcome was carried out with number of lobes with the patterns +A/-H, -A/+H, +A/+H respectively as predictors. The model was mutually adjusted along with adjustment for age and sex. A sensitivity analysis with a -score dichotomization at -0.1 and -0.5 and dichotomization regarding number of lobes affected at one and three lobes was done.

Results: Median follow-up time was 420 days [IQR: 387-461 days] and 50 patients progressed. Patients with two or more lobes affected by the pattern +A/+H compared to patients with 0-1 lobes affected had a statistically significant increased risk of progression (odds ratio, 95 % confidence interval: 4.33, 1.90-9.86) in a multivariable model. The model was partially robust to the applied sensitivity analysis.

Conclusion: Combined atrophy and hypometabolism as assessed by MRI and [F]FDG-PET in patients under suspicion of neurodegenerative disease predicts progression over 1 year.
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http://dx.doi.org/10.7717/peerj.9498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354835PMC
July 2020

Molecular characterization of the calcium release channel deficiency syndrome.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA.

We identified a potentially novel homozygous duplication involving the promoter region and exons 1-4 of the gene encoding type 2 cardiac ryanodine receptor (RYR2) that is responsible for highly penetrant, exertion-related sudden deaths/cardiac arrests in the Amish community without an overt phenotype to suggest RYR2-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). Homozygous RYR2 duplication (RYR2-DUP) induced pluripotent stem cell cardiomyocytes (iPSC-CMs) were generated from 2 unrelated patients. There was no difference in baseline Ca2+ handling measurements between WT-iPSC-CM and RYR2-DUP-iPSC-CM lines. However, compared with WT-iPSC-CMs, both patient lines demonstrated a dramatic reduction in caffeine-stimulated and isoproterenol-stimulated (ISO-stimulated) Ca2+ transient amplitude, suggesting RyR2 loss of function. There was a greater than 50% reduction in RYR2 transcript/RyR2 protein expression in both patient iPSC-CMs compared with WT. Delayed afterdepolarization was observed in the RYR2-DUP-iPSC-CMs but not in the WT-iPSC-CMs. Compared with WT-iPSC-CMs, there was significantly elevated arrhythmic activity in the RYR2-DUP-iPSC-CMs in response to ISO. Nadolol, propranolol, and flecainide reduced erratic activity by 8.5-fold, 6.8-fold, and 2.4-fold, respectively, from ISO challenge. Unlike the gain-of-function mechanism observed in RYR2-mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in RYR2 transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive to catecholamines and caffeine.
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http://dx.doi.org/10.1172/jci.insight.135952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455073PMC
August 2020

Loss of ventricular preexcitation during noninvasive testing does not exclude high-risk accessory pathways: A multicenter study of WPW in children.

Heart Rhythm 2020 10 1;17(10):1729-1737. Epub 2020 Jun 1.

Division of Pediatric Cardiology, Advocate Children's Heart Institute at Advocate Children's Hospital, Oak Lawn, Illinois.

Background: Abrupt loss of ventricular preexcitation on noninvasive evaluation, or nonpersistent preexcitation, in Wolff-Parkinson-White syndrome (WPW) is thought to indicate a low risk of life-threatening events.

Objective: The purpose of this study was to compare accessory pathway (AP) characteristics and occurrences of sudden cardiac arrest (SCA) and rapidly conducted preexcited atrial fibrillation (RC-AF) in patients with nonpersistent and persistent preexcitation.

Methods: Patients 21 years or younger with WPW and invasive electrophysiology study (EPS) data, SCA, or RC-AF were identified from multicenter databases. Nonpersistent preexcitation was defined as absence/sudden loss of preexcitation on electrocardiogram, Holter monitoring, or exercise stress test. RC-AF was defined as clinical preexcited atrial fibrillation with shortest preexcited R-R interval (SPERRI) ≤ 250 ms. AP effective refractory period (APERP), SPERRI at EPS , and shortest preexcited paced cycle length (SPPCL) were collected. High-risk APs were defined as APERP, SPERRI, or SPPCL ≤ 250 ms.

Results: Of 1589 patients, 244 (15%) had nonpersistent preexcitation and 1345 (85%) had persistent preexcitation. There were no differences in sex (58% vs 60% male; P=.49) or age (13.3±3.6 years vs 13.1±3.9 years; P=.43) between groups. Although APERP (344±76 ms vs 312±61 ms; P<.001) and SPPCL (394±123 ms vs 317±82 ms; P<.001) were longer in nonpersistent vs persistent preexcitation, there was no difference in SPERRI at EPS (331±71 ms vs 316±73 ms; P=.15). Nonpersistent preexcitation was associated with fewer high-risk APs (13% vs 23%; P<.001) than persistent preexcitation. Of 61 patients with SCA or RC-AF, 6 (10%) had nonpersistent preexcitation (3 SCA, 3 RC-AF).

Conclusion: Nonpersistent preexcitation was associated with fewer high-risk APs, though it did not exclude the risk of SCA or RC-AF in children with WPW.
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http://dx.doi.org/10.1016/j.hrthm.2020.05.035DOI Listing
October 2020

Evaluating 2-[F]FDG-PET in differential diagnosis of dementia using a data-driven decision model.

Neuroimage Clin 2020 24;27:102267. Epub 2020 Apr 24.

Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

2-[F]fluoro-2-deoxy-d-glucose positron emission tomography (2-[F]FDG-PET) has an emerging supportive role in dementia diagnostic as distinctive metabolic patterns are specific for Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). Previous studies have demonstrated that a data-driven decision model based on the disease state index (DSI) classifier supports clinicians in the differential diagnosis of dementia by using different combinations of diagnostic tests and biomarkers. Until now, this model has not included 2-[F]FDG-PET data. The objective of the study was to evaluate 2-[F]FDG-PET biomarkers combined with commonly used diagnostic tests in the differential diagnosis of dementia using the DSI classifier. We included data from 259 subjects diagnosed with AD, DLB, FTD, vascular dementia (VaD), and subjective cognitive decline from two independent study cohorts. We also evaluated three 2-[F]FDG-PET biomarkers (anterior vs. posterior index (API-PET), occipital vs. temporal index, and cingulate island sign) to improve the classification accuracy for both FTD and DLB. We found that the addition of 2-[F]FDG-PET biomarkers to cognitive tests, CSF and MRI biomarkers considerably improved the classification accuracy for all pairwise comparisons of DLB (balanced accuracies: DLB vs. AD from 64% to 77%; DLB vs. FTD from 71% to 92%; and DLB vs. VaD from 71% to 84%). The two 2-[F]FDG-PET biomarkers, API-PET and occipital vs. temporal index, improved the accuracy for FTD and DLB, especially as compared to AD. Moreover, different combinations of diagnostic tests were valuable to differentiate specific subtypes of dementia. In conclusion, this study demonstrated that the addition of 2-[F]FDG-PET to commonly used diagnostic tests provided complementary information that may help clinicians in diagnosing patients, particularly for differentiating between patients with FTD, DLB, and AD.
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http://dx.doi.org/10.1016/j.nicl.2020.102267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229490PMC
March 2021

EANM practice guideline/SNMMI procedure standard for dopaminergic imaging in Parkinsonian syndromes 1.0.

Eur J Nucl Med Mol Imaging 2020 07 9;47(8):1885-1912. Epub 2020 May 9.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Purpose: This joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes.

Methods: Currently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [F]fluorodopa imaging in this setting are still lacking.

Conclusion: All these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.
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http://dx.doi.org/10.1007/s00259-020-04817-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300075PMC
July 2020

Pearls and Pitfalls in Interpretation of 68Ga-DOTATOC PET Imaging.

Clin Nucl Med 2020 Jun;45(6):e279-e280

From the Departments of Clinical Physiology, Nuclear Medicine, and PET.

DOTA-D-Phe-Tyr-octreotide labeled with Ga (Ga-DOTATOC) is the commonly used PET tracer for imaging meningioma because of its high affinity to somatostatin receptor subtype 2 (SSTR2) and an established imaging modality for planning radiation and radionuclide therapy. However, SSTR2 is not an exclusive marker for meningioma, and not all meningiomas express high levels of SSTR2. The SSTR2 expression has been reported in other intracranial tumors, for example, glioma, pituitary adenoma, medullablastoma, primitive neuroectodermal tumors, and hemangioblastoma leading to a significant risk of misinterpretation of PET/CT findings. We present 2 cases with similar Ga-DOTATOC uptakes in 2 distinct etiologies, for example, cerebral lymphoma and meningioma.
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http://dx.doi.org/10.1097/RLU.0000000000003012DOI Listing
June 2020

Pharmacokinetic analysis of [Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2.

Eur J Nucl Med Mol Imaging 2020 10 13;47(11):2577-2588. Epub 2020 Mar 13.

Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Purpose: DOTA-D-Phe-Tyr-octreotide with gallium-68 ([Ga]Ga-DOTA-TOC) is one of the PET tracers that forms the basis for peptide receptor radionuclide therapy based on somatostatin receptor subtype 2 (SSTR2) expression in meningiomas. Yet, the quantitative relationship between [Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [Ga]Ga-DOTA-TOC PET metric(s) as imaging surrogate(s) of the receptor binding in meningiomas by correlating the PET results with SSTR2 expression from surgical specimens. We additionally investigated possible influences of secondary biological factors such as vascularization, inflammation and proliferation.

Methods: Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUV, SUV) with and without normalization to reference regions, and quantitative measurements derived from kinetic modelling using a reversible two-tissue compartment model with the fractional blood volume (V). Expressions of SSTR2 and proliferation (Ki-67, phosphohistone-H3, proliferating cell nuclear antigen) were determined by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR), while biomarkers of vascularization (vascular endothelial growth factor A (VEGFA), endothelial marker CD34) and inflammation (cytokine interleukin-18, microglia/macrophage-specific marker CD68) by qPCR.

Results: Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [Ga]Ga-DOTA-TOC PET metrics showed significant associations with SSTR2 protein, while all PET metrics were positively correlated with SSTR2 mRNA with the best results for mean tumour-to-blood ratio (TBR) (r = 0.757, P = 0.001) and SUV (r = 0.714, P = 0.003). Significant positive correlations were also found between [Ga]Ga-DOTA-TOC PET metrics, and VEGFA and V. SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation.

Conclusion: [Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBR being the best PET metric for assessing SSTR2.
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http://dx.doi.org/10.1007/s00259-020-04759-1DOI Listing
October 2020
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