[15O]H2O myocardial perfusion positron emission tomography: Added value of relative stress perfusion deficit in the prediction of significant coronary artery stenosis in a mixedpopulation.

BACKGROUND: It remains unknown whether estimation of the relative stress perfusion deficit offers added value in the prediction of significant coronary artery stenosis in myocardial perfusion imaging with [15O]H2O positron emission tomography (PET) in a population with high prevalence of established cardiac disease. METHODS: During eight months, we consecutively included all patients undergoing [15O]H2O PET and subsequent invasive coronary angiography (ICA). Significant stenosis was defined from ICA as fractional flow reserve ≤.8 or coronary artery narrowing of ≥70%. We calculated absolute and relative total perfusion deficits (aTPD and rTPD, respectively) as semiquantitative measures of the extent and severity of reduced stress perfusion. A multivariate logistic regression analysis was performed to test the adjusted associations (odds ratio (OR) with 95% CI) with significant coronary artery stenosis. RESULTS: Of 800 patients undergoing [15O]H2O PET, 144 underwent ICA, where 142 patients had aTPD of ≥3% and 79 (55%) of these had at least one significant stenosis. In an adjusted analysis, rTPD (OR10% increase = 2.12 (1.44-3.12), P < .001), previous coronary artery bypass grafting (CABG) (OR = .11 (.03-.36), P < .001) and reduced left ventricular ejection fraction (LVEF) (OR = .25 (.08-.84), P = .02) were independently associated with significant stenosis, whereas the association with aTPD (OR10% increase = 1.14 (.98-1.32), P = .08) was modest. CONCLUSIONS: In the presence of an absolute perfusion deficit (aTPD of ≥3%), rTPD may improve the prediction of significant stenosis in a heterogeneous population of patients examined with [15O]H2O PET. Furthermore, previous CABG and reduced LVEF are associated with nonstenotic perfusion deficiencies, suggesting caution when interpreting myocardial perfusion imaging in such patients.

Long-term prognostic value of [15O]H2O PET imaging in patients suspected for cerebral hemodynamic insufficiency.

OBJECTIVES: Quantitative regional cerebral perfusion (rCBF) measurements using [15O]H2O PET with arterial cannulation and acetazolamide (ACZ) challenge have been reserved to identify high-risk patients that are candidates for by-pass operation. We aimed to assess the prognostic value of various parameters in quantitative [15O]H2O PET measurements in patients not subsequently undergoing surgery. METHODS: We identified 32 eligible patients who underwent [15O]H2O brain PET imaging for suspicion of hemodynamic insufficiency between 2009 and 2020. Cerebrovascular events were defined as new ischemic lesions on MRI, stroke, transient ischemic attack, vascular dementia. Follow-up period was 91 months (range: 26-146). rCBF before (rCBFbase) and after (rCBFacz) ACZ challenge and the relative increase (CVR), were examined in the anterior (ACA), middle (MCA), and posterior (PCA) cerebral artery territories of the affected hemisphere, and the most recent MRI scans were scored for infarcts and white matter lesions. RESULTS: Receiver operating characteristic (ROC) curve analysis showed higher prognostic accuracy for rCBFacz(AUC:0.82) compared to CVR (AUC:0.72) and rCBFbase (AUC:0.77). ROC AUC, optimal thresholds (and corresponding sensitivity/specificity/accuracy) for rCBFacz after ACZ in individual territories were 0.79 and 37.8 mL 100g-1 min-1 (0.81/0.63/0.72) for the ACA, 0.84 and 32 mL 100g-1 min-1 (0.81/0.75/0.78) for the MCA, and 0.70 and 43.9 ml/(mL 100g-1 min-1 (0.81/0.43/0,62) for the PCA. Kaplan Meier survival curve showed longer event-free survival in patients with rCBFacz below cut-off (p=0.007). In multivariate analysis rCBFacz remained a significant predictor when correcting for age. CONCLUSION: Quantitative rCBF measurements after ACZ challenge with [15O]H2O PET provided high prognostic value for future cerebrovascular events.

Quantitative cellular changes in multiple system atrophy brains.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterised by a combined symptomatology of parkinsonism, cerebellar ataxia, autonomic failure and corticospinal dysfunction. In brains of MSA patients, the hallmark lesion is the aggregation of misfolded alpha-synuclein in oligodendrocytes. Even though the underlying pathological mechanisms remain poorly understood, the evidence suggests that alpha-synuclein aggregation in oligodendrocytes may contribute to the neurodegeneration seen in MSA. The primary aim of this review is to summarise the published stereological data on the total number of neurons and glial cell subtypes (oligodendrocytes, astrocytes and microglia) and volumes in brains from MSA patients. Thus, we include in this review exclusively the reports of unbiased quantitative data from brain regions including the neocortex, nuclei of the cerebrum, the brainstem and the cerebellum. Furthermore, we compare and discuss the stereological results in the context of imaging findings and MSA symptomatology. In general, the stereological results agree with the common neuropathological findings of neurodegeneration and gliosis in brains from MSA patients and support a major loss of nigrostriatal neurons in MSA patients with predominant parkinsonism (MSA-P), as well as olivopontocerebellar atrophy in MSA patients with predominant cerebellar ataxia (MSA-C). Surprisingly, the reports indicate only a minor loss of oligodendrocytes in sub-cortical regions of the cerebrum (glial cells not studied in the cerebellum) and negligible changes in brain volumes. In the past decades, the use of stereological methods has provided a vast amount of accurate information on cell numbers and volumes in the brains of MSA patients. Combining different techniques such as stereology and diagnostic imaging (e.g. MRI, PET and SPECT) with clinical data allows for a more detailed interdisciplinary understanding of the disease and illuminates the relationship between neuropathological changes and MSA symptomatology.

82Rb and [15O]H2O myocardial perfusion PET imaging: a prospective head to head comparison.

BACKGROUND: 82Rb PET and [15O]H2O PET are both validated tracers for myocardical perfusion imaging but have not previously been compared clinically. During our site's transition from 82Rb to [15O]H2O PET, we performed a head-to-head comparison in a mixed population with suspected ischemic heart disease. METHODS: A total of 37 patients referred for perfusion imaging due to suspicion of coronary stenosis were examined with both 82Rb and [15O]H2O PET on the same day in rest and during adenosine-induced stress. The exams were rated by two blinded readers as normal, regional ischemia, globally reduced myocardial perfusion, or myocardial scarring. For [15O]H2O PET, regional ischemia was defined as two neighboring segments with average stress perfusion ≤ 2.3 mL/(min·g). Further, we evaluated a total perfusion deficit (TPD) of ≥ 10% as a more conservative marker of ischemia. RESULTS: [15O]H2O PET identified more patients with regional ischemia: 17(46%) vs 9(24%), agreement: 59% corresponding to a Cohen's kappa of .31 [95%CI .08-.53], (P < .001). Using the more conservative TPD ≥ 10%, the agreement increased to 86% corresponding to a kappa of .62 [95%CI .33-.92], (P = .001). For the subgroup of patients with no known heart disease (n = 18), the agreement was 94%. Interrater agreement was 95% corresponding to a kappa of .89 [95%CI .74-1.00] (P < .001). CONCLUSIONS: In clinical transition from 82Rb to [15O]H2O PET, it is important to take into account the higher frequency of patients with regional ischemia detected by [15O]H2O PET.

Non-invasive quantification of cerebral glucose metabolism using Gjedde-Patlak plot and image-derived input function from the aorta.

INTRODUCTION: We aimed at evaluating a Gjedde-Patlak plot and non-invasive image-derived input functions (IDIF) from the aorta to quantify cerebral glucose metabolic rate (CMRglc) in comparison to the reference standard based on sampling the arterial input function (AIF). METHOD: Six healthy subjects received 200 MBq [18F]FDG simultaneously with the initiation of a three-part dynamic PET recording consisting of a 15 min-recording of the aorta, a 40 min-recording of the brain and finally 2 min-recording of the aorta. Simultaneously, the arterial 18F concentration was measured via arterial cannulation. Regions of interest were drawn in the aorta and the brain and time-activity curves extracted. The IDIF was obtained by fitting a triple exponential function to the aorta time-activity curve after the initial peak including the late aorta frame, thereby interpolating the arterial blood activity concentration during the brain scan. CMRglc was calculated from Gjedde-Patlak plots using AIF and IDIF, respectively and the predictive value was examined. Results from frontal cortex, insula, hippocampus and cerebellum were compared by paired t-test and agreement between the methods was analyzed by Bland-Altman plot statistics. RESULTS: There was a strong linear relationship and an excellent agreement between the methods (mean±SD of CMRglcIDIF (µmol 100 g-1 min-1), mean difference, mean relative difference, 95% limits of agreement): frontal cortex: 30.8 ± 3.3, 0.5, 2.2%, [-1,6:2.5], insula: 25.4 ± 2.2, 0.4, 2.4%, [-1.4:2.2], hippocampus: 16.9 ± 1.2, 0.4, 3.8%, [-1.1:2.0] and cerebellum: 23.4 ± 1.9, 0.5, 3.1%, [-1.4:2.5]). CONCLUSION: We found excellent agreement between CMRglc obtained with an IDIF from the aorta and the reference standard with AIF. A non-invasive three-part dynamic [18F]FDG PET recording is feasible as a non-invasive alternative for reliable quantification of cerebral glucose metabolism in all scanner systems. This is useful in patients with presumed global cerebral changes owing to systemic disease or for the monitoring of treatment effects.

Joint EANM/SIOPE/RAPNO practice guidelines/SNMMI procedure standards for imaging of paediatric gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0.

Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is the most commonly used radiopharmaceutical for PET imaging. For oncological brain imaging, different amino acid PET radiopharmaceuticals have been introduced in the last years. The purpose of this document is to provide imaging specialists and clinicians guidelines for indication, acquisition, and interpretation of [18F]FDG and radiolabelled amino acid PET in paediatric patients affected by brain gliomas. There is no high level of evidence for all recommendations suggested in this paper. These recommendations represent instead the consensus opinion of experienced leaders in the field. Further studies are needed to reach evidence-based recommendations for the applications of [18F]FDG and radiolabelled amino acid PET in paediatric neuro-oncology. These recommendations are not intended to be a substitute for national and international legal or regulatory provisions and should be considered in the context of good practice in nuclear medicine. The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group and the Response Assessment in Paediatric Neuro-Oncology (RAPNO) working group. They summarize also the views of the Neuroimaging and Oncology and Theranostics Committees of the EANM and reflect recommendations for which the EANM and other societies cannot be held responsible.

Diagnostic yield of simultaneous dynamic contrast-enhanced magnetic resonance perfusion measurements and [18F]FET PET in patients with suspected recurrent anaplastic astrocytoma and glioblastoma.

PURPOSE: Both amino acid positron emission tomography (PET) and magnetic resonance imaging (MRI) blood volume (BV) measurements are used in suspected recurrent high-grade gliomas. We compared the separate and combined diagnostic yield of simultaneously acquired dynamic contrast-enhanced (DCE) perfusion MRI and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET in patients with anaplastic astrocytoma and glioblastoma following standard therapy. METHODS: A total of 76 lesions in 60 hybrid [18F]FET PET/MRI scans with DCE MRI from patients with suspected recurrence of anaplastic astrocytoma and glioblastoma were included retrospectively. BV was measured from DCE MRI employing a 2-compartment exchange model (2CXM). Diagnostic performances of maximal tumour-to-background [18F]FET uptake (TBRmax), maximal BV (BVmax) and normalised BVmax (nBVmax) were determined by ROC analysis using 6-month histopathological (n = 28) or clinical/radiographical follow-up (n = 48) as reference. Sensitivity and specificity at optimal cut-offs were determined separately for enhancing and non-enhancing lesions. RESULTS: In progressive lesions, all BV and [18F]FET metrics were higher than in non-progressive lesions. ROC analyses showed higher overall ROC AUCs for TBRmax than both BVmax and nBVmax in both lesion-wise (all lesions, p = 0.04) and in patient-wise analysis (p < 0.01). Combining TBRmax with BV metrics did not increase ROC AUC. Lesion-wise positive fraction/sensitivity/specificity at optimal cut-offs were 55%/91%/84% for TBRmax, 45%/77%/84% for BVmax and 59%/84%/72% for nBVmax. Combining TBRmax and best-performing BV cut-offs yielded lesion-wise sensitivity/specificity of 75/97%. The fraction of progressive lesions was 11% in concordant negative lesions, 33% in lesions only BV positive, 64% in lesions only [18F]FET positive and 97% in concordant positive lesions. CONCLUSION: The overall diagnostic accuracy of DCE BV imaging is good, but lower than that of [18F]FET PET. Adding DCE BV imaging did not improve the overall diagnostic accuracy of [18F]FET PET, but may improve specificity and allow better lesion-wise risk stratification than [18F]FET PET alone.

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

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.

In vivo imaging of cell proliferation in meningioma using 3'-deoxy-3'-[18F]fluorothymidine PET/MRI.

PURPOSE: Positron emission tomography (PET) with 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) provides a noninvasive assessment of tumour proliferation in vivo and could be a valuable imaging modality for assessing malignancy in meningiomas. We investigated a range of static and dynamic [18F]FLT metrics by correlating the findings with cellular biomarkers of proliferation and angiogenesis. METHODS: Seventeen prospectively recruited adult patients with intracranial meningiomas underwent a 60-min dynamic [18F]FLT PET following surgery. Maximum and mean standardized uptake values (SUVmax, SUVmean) with and without normalization to healthy brain tissue and blood radioactivity obtained from 40 to 60 min summed dynamic images (PET40-60) and ~ 60-min blood samples were calculated. Kinetic modelling using a two-tissue reversible compartmental model with a fractioned blood volume (VB) was performed to determine the total distribution volume (VT). Expressions of proliferation and angiogenesis with key parameters including Ki-67 index, phosphohistone-H3 (phh3), MKI67, thymidine kinase 1 (TK1), proliferating cell nuclear antigen (PCNA), Kirsten RAt Sarcoma viral oncogene homolog (KRAS), TIMP metallopeptidase inhibitor 3 (TIMP3), and vascular endothelial growth factor A (VEGFA) were determined by immunohistochemistry and/or quantitative polymerase chain reaction. RESULTS: Immunohistochemistry revealed 13 World Health Organization (WHO) grade I and four WHO grade II meningiomas. SUVmax and SUVmean normalized to blood radioactivity from PET40-60 and blood sampling, and VT were able to significantly differentiate between WHO grades with the best results for maximum and mean tumour-to-whole-blood ratios (sensitivity 100%, specificity 94-95%, accuracy 99%; P = 0.003). Static [18F]FLT metrics were significantly correlated with proliferative biomarkers, especially Ki-67 index, phh3, and TK1, while no correlations were found with VEGFA or VB. Using Ki-67 index with a threshold > 4%, the majority of [18F]FLT metrics showed a high ability to identify aggressive meningiomas with SUVmean demonstrating the best performance (sensitivity 80%, specificity 81%, accuracy 80%; P = 0.024). CONCLUSION: [18F]FLT PET could be a useful imaging modality for assessing cellular proliferation in meningiomas.

Pharmacokinetic analysis of [68Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2.

PURPOSE: DOTA-D-Phe1-Tyr3-octreotide with gallium-68 ([68Ga]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 [68Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [68Ga]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 [68Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUVmax, SUVmean) 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 (VB). 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 [68Ga]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 (TBRmean) (r = 0.757, P = 0.001) and SUVmean (r = 0.714, P = 0.003). Significant positive correlations were also found between [68Ga]Ga-DOTA-TOC PET metrics, and VEGFA and VB. SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [68Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation. CONCLUSION: [68Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBRmean being the best PET metric for assessing SSTR2.

Quantifying the Financial Savings of Motion Correction in Brain MRI: A Model-Based Estimate of the Costs Arising From Patient Head Motion and Potential Savings From Implementation of Motion Correction.

BACKGROUND: Patient head motion is a major concern in clinical brain MRI, as it reduces the diagnostic image quality and may increase examination time and cost. PURPOSE: To investigate the prevalence of MR images with significant motion artifacts on a given clinical scanner and to estimate the potential financial cost savings of applying motion correction to clinical brain MRI examinations. STUDY TYPE: Retrospective. SUBJECTS: In all, 173 patients undergoing a PET/MRI dementia protocol and 55 pediatric patients undergoing a PET/MRI brain tumor protocol. The total scan time of the two protocols were 17 and 40 minutes, respectively. FIELD STRENGTH/SEQUENCES: 3 T, Siemens mMR Biograph, MPRAGE, DWI, T1 and T2 -weighted FLAIR, T2 -weighted 2D-FLASH, T2 -weighted TSE. ASSESSMENT: A retrospective review of image sequences from a given clinical MRI scanner was conducted to investigate the prevalence of motion-corrupted images. The review was performed by three radiologists with different levels of experience using a three-step semiquantitative scale to classify the quality of the images. A total of 1013 sequences distributed on 228 MRI examinations were reviewed. The potential cost savings of motion correction were estimated by a cost estimation for our country with assumptions. STATISTICAL TEST: The cost estimation was conducted with a 20% lower and upper bound on the model assumptions to include the uncertainty of the assumptions. RESULTS: 7.9% of the sequences had motion artifacts that decreased the interpretability, while 2.0% of the sequences had motion artifacts causing the images to be nondiagnostic. The estimated annual cost to the clinic/hospital due to patient head motion per scanner was $45,066 without pediatric examinations and $364,242 with pediatric examinations. DATA CONCLUSION: The prevalence of a motion-corrupted image was found in 2.0% of the reviewed sequences. Based on the model, repayment periods are presented as a function of the price for applying motion correction and its performance. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 6 J. Magn. Reson. Imaging 2020;52:731-738.

A Novel TTBK2 De Novo Mutation in a Danish Family with Early-Onset Spinocerebellar Ataxia.

Spinocerebellar ataxia type 11 (SCA11) is rare and has previously been described in four families worldwide. We report a Danish family with onset of symptoms in early childhood and affected family members in two generations. The proband, a Danish female born in 1968, and family members were examined. Exome sequencing was performed and a "movement disorders" gene panel consisting of approximately 200 genes was used for filtering, while Sanger sequencing was used for subsequent testing for the mutation in the family. Onset of symptoms in affected family members was in early childhood. A novel frameshift mutation (c.1205_1207delinsA) in the tau-tubulin kinase 2 encoding gene, TTBK2, was identified, which was compatible with a diagnosis of SCA11. The mutation was subsequently identified in her two affected sons but not in the unaffected parents or her unaffected brother. This report further delineates the phenotypic spectrum of the rare SCA11 disease. In contrast to previously reported cases, onset of symptoms was in early childhood and the mutation was de novo in the proband.

A prospective clinical study of the influence of oral protein intake on [18F]FET-PET uptake and test-retest repeatability in glioma.

BACKGROUND: O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) scanning is used in routine clinical management and evaluation of gliomas with a recommended 4 h prior fasting. Knowledge of test-retest variation of [18F]FET PET imaging uptake metrics and the impact of accidental protein intake can be critical for interpretation. The aim of this study was to investigate the repeatability of [18F]FET-PET metrics and to assess the impact of protein-intake prior to [18F]FET PET scanning of gliomas. RESULTS: Test-retest variability in the non-protein group was good with absolute (and relative) upper and lower limits of agreement of + 0.15 and - 0.13 (+ 9.7% and - 9.0%) for mean tumour-to-background ratio (TBRmean), + 0.43 and - 0.28 (+ 19.6% and - 11.8%) for maximal tumour-to-background ratio (TBRmax), and + 2.14 cm3 and - 1.53 ml (+ 219.8% and - 57.3%) for biological tumour volume (BTV). Variation was lower for uptake ratios than for BTV. Protein intake was associated with a 27% increase in the total sum of plasma concentration of the L-type amino acid transporter 1 (LAT1) relevant amino acids and with decreased standardized uptake value (SUV) in both healthy appearing background brain tissue (mean SUV - 25%) and in tumour (maximal SUV - 14%). Oral intake of 24 g of protein 1 h prior to injection of tracer tended to increase variability, but the effects on derived tumour metrics TBRmean and TBRmax were only borderline significant, and changes generally within the variability observed in the group with no protein intake. CONCLUSION: The test-retest repeatability was found to be good, and better for TBRmax and TBRmean than BTV, with the methodological limitation that tumour growth may have influenced results. Oral intake of 24 g of protein one hour before a [18F]FET PET scan decreases uptake of [18F]FET in both tumour and in healthy appearing brain, with no clinically significant difference on the most commonly used tumour metrics.

The 5-HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans.

The cerebral serotonin (5-HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5-HT type 4 receptor (5-HT4 R) facilitates memory and learning and further that the 5-HT4 R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5-HT4 R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [(11) C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5-HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BPND , (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BPND and delayed recall (p = 0.014). These findings provide evidence that the 5-HT4 R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory.

Diagnostic accuracy of cerebral [18F]FDG PET in atypical parkinsonism.

BACKGROUND: Atypical parkinsonism (AP) often presents with Parkinson's symptoms but has a much worse long-term prognosis. The diagnosis is presently based on clinical criteria, but a cerebral positron emission tomography (PET) scan with [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG) may assist in the diagnosis of AP such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Lewy body dementia (DLB). Only few studies have evaluated the sensitivity and specificity of [18F]FDG PET for separating the diseases in a mixed patient population, which we aim to assess in a retrospective material. RESULTS: We identified 156 patients referred for a cerebral [18F]FDG PET for suspicion of AP during 2017-2019. The [18F]FDG PET was analysed by a nuclear medicine specialist blinded to clinical information but with access to dopamine transporter imaging. The reference standard was the follow-up clinical diagnosis (follow-up: 6-72 months). The overall accuracy for correct classification was 74%. Classification sensitivity (95% confidence interval, CI) and specificity (95% CI) for MSA (n = 20) were 1.00 (0.83-1.00) and 0.91 (0.85-0.95), for DLB/Parkinson with dementia (PDD) (n = 26) were 0.81 (0.61-0.93) and 0.97 (0.92-0.99) and for CBD/PSP (n = 68) were 0.62 (0.49-0.73) and 0.97 (0.90-0.99). CONCLUSIONS: Our results support the additional use of [18F]FDG PET for the clinical diagnosis of AP with moderate to high sensitivity and specificity. Use of [18F]FDG PET may be beneficial for prognosis and supportive treatment of the patients and useful for future clinical treatment trials.

Sertraline treatment influences [18F]FE-PE2I PET imaging for Parkinsonism.

BACKGROUND: The dopamine transporter (DaT) PET ligand [18F]FE-PE2I is used to aid the diagnosis of Parkinson's disease. After encountering four patients with a history of daily sertraline use, who all showed atypical findings on [18F]FE-PE2I PET, we suspected that the selective serotonin reuptake inhibitor (SSRI), sertraline, might interfere with the results and lead to globally reduced striatal [18F]FE-PE2I binding due to sertraline's high affinity for DaT. METHODS: We rescanned the four patients with [18F]FE-PE2I PET after a 5-day sertraline pause. Sertraline plasma concentration was estimated based on body weight and dose, and specific binding ratios (SBR) in caudate nucleus, known to be more preserved in Parkinson's, were used to estimate the effect on tracer binding. Comparison was made to a patient with [18F]FE-PE2I PET before and after a 7-day Modafinil pause. RESULTS: We found a significant effect of sertraline on caudate nucleus SBR (p = 0.029). The effect showed a linear dose-dependent relationship that corresponds to a reduction in SBR by 0.32 or 0.44 for a 75 kg male or a 65 kg female, respectively, taking a daily dose of 50 mg sertraline. CONCLUSION: Sertraline is one of the most commonly used antidepressants and in contrast to other SSRI's, sertraline show high affinity for DaT. We recommend that sertraline treatment is taken into account when patients are undergoing [18F]FE-PE2I PET especially in patients showing apparent globally reduced PE2I binding. If tolerable, pausing of the sertraline treatment should be considered, especially for doses above 50 mg/day.

Bone Turnover in Patients with Chronic Kidney Disease Stage 5D and Healthy Controls - a Quantitative [18F]Fluoride PET Study.

BACKGROUND: Chronic kidney disease (CKD) is prevalent in the aging population and increases the risk of fracture 2-4 times. We compared optimized quantitative [18F]fluoride PET/CT methods to the reference standard with arterial input function (AIF) to identify a clinically accessible method for evaluation of bone turnover in patients with CKD. METHODS: Ten patients on chronic hemodialysis treatment and ten control patients were recruited. A dynamic 60-min [18F]fluoride PET scan was obtained from the 5th lumbar vertebra to the proximal femur simultaneously with arterial blood sampling to achieve an AIF. Individual AIFs were time-shifted to compute a population curve (PDIF). Bone and vascular volumes-of-interest (VOIs) were drawn, and an image-derived-input-function (IDIF) was extracted. PDIF and IDIF were scaled to plasma. Bone turnover (Ki) was calculated with the AIF, PDIF, and IDIF and bone VOIs using a Gjedde-Patlak plot. Input methods were compared using correlations and precision errors. RESULTS: The calculated Ki from the five non-invasive methods all correlated to the Ki from the AIF method with the PDIF scaled to a single late plasma sample showing the highest correlations (r > 0.94), and the lowest precision error of 3-5%. Furthermore, the femoral bone VOI's correlated positively to p-PTH and showed significant differences between patients and controls. CONCLUSIONS: Dynamic 30 min [18F]fluoride PET/CT with a population based input curve scaled to a single venous plasma sample is a feasible and precise non-invasive diagnostic method for the assessment of bone turnover in patients with CKD. The method may potentially allow for earlier and more precise diagnosis and may be useful for assessment of treatment effects, which is crucial for development of future treatment strategies.

Myocardial Flow Reserve, an Independent Prognostic Marker of All-Cause Mortality Assessed by 82Rb PET Myocardial Perfusion Imaging: A Danish Multicenter Study.

BACKGROUND: Rubidium-82 positron emission tomography (82Rb PET) myocardial perfusion imaging is used in clinical practice to quantify regional perfusion defects. Additionally, 82Rb PET provides a measure of absolute myocardial flow reserve (MFR), describing the vasculature state of health. We assessed whether 82Rb PET-derived MFR is associated with all-cause mortality independently of the extent of perfusion defects. METHODS: We conducted a multicenter clinical registry-based study of patients undergoing 82Rb PET myocardial perfusion imaging on suspicion of chronic coronary syndromes. Patients were followed up in national registries for the primary outcome of all-cause mortality. Global MFR ≤2 was considered reduced. RESULTS: Among 7169 patients studied, 38.1% were women, the median age was 69 (IQR, 61-76) years, and 39.0% had MFR ≤2. A total of 667 (9.3%) patients died during a median follow-up of 3.1 (IQR, 2.6-4.0) years, more in patients with MFR ≤2 versus MFR >2 (15.7% versus 5.2%; P<0.001). MFR ≤2 was associated with all-cause mortality across subgroups defined by the extent of perfusion defects (all P<0.05). In a Cox survival regression model adjusting for sex, age, comorbidities, kidney function, left ventricular ejection fraction, and perfusion defects, MFR ≤2 was a robust predictor of mortality with a hazard ratio of 1.62 (95% CI, 1.31-2.02; P<0.001). Among patients with no reversible perfusion defects (n=3101), MFR ≤2 remained strongly associated with mortality (hazard ratio, 1.86 [95% CI, 1.26-2.73]; P<0.01). The prognostic value of impaired MFR was similar for cardiac and noncardiac death. CONCLUSIONS: MFR ≤2 predicts all-cause mortality independently of the extent of perfusion defects. Our results support the inclusion of MFR when assessing the prognosis of patients suspected of chronic coronary syndromes.

Coronary Microvascular Disease Assessed by 82-Rubidium Positron Emission Tomography Myocardial Perfusion Imaging Is Associated With Small Vessel Disease of the Kidney and Brain.

Background Coronary microvascular disease (CMD) may be part of a systemic small vessel disease that also manifests as neurological impairment and kidney disease. However, clinical evidence supporting a potential link is scarce. We assessed whether CMD is associated with an increased risk of small vessel disease in the kidney and brain. Methods and Results A retrospective multicenter (n=3) study of patients clinically referred to 82-rubidium positron emission tomography myocardial perfusion imaging was conducted between January 2018 and August 2020. Exclusion criterion was reversible perfusion defects >5%. CMD was defined as myocardial flow reserve (MFR) ≤2. The primary outcome, microvascular event, was defined by hospital contact for chronic kidney disease, stroke, or dementia. Among 5122 patients, 51.7% were men, median age 69.0 [interquartile range, 60.0-75.0] years, 11.0% had left ventricular ejection fraction ≤40%, and 32.4% had MFR ≤2. MFR was associated with baseline estimated glomerular filtration rate after multivariable adjustment (ß=0.04 [95% CI, 0.03-0.05]; P<0.001). During a median follow-up of 3.05 years, 383 (7.5%) patients suffered an event (253 cerebral and 130 renal), more frequently in patients with MFR ≤2 versus MFR >2 (11.6% versus 5.5%, P<0.001). MFR ≤2 was associated to outcome with a hazard ratio (HR) of 2.30 (95% CI, 1.88-2.81, P<0.001) and an adjusted HR of 1.62 (95% CI, 1.32-2.00, P<0.001). Results were consistent across subgroups defined by presence of irreversible perfusion defects, estimated glomerular filtration rate, diabetes, left ventricular ejection fraction, and previous revascularization. Conclusions This is the first large-scale cohort study to link CMD to microvascular events in the kidney and brain. Data support the hypothesis that CMD is part of a systemic vascular disorder.

Cerebral Metabolic Rate of Glucose and Cognitive Tests in Long COVID Patients.

BACKGROUND: Common long-term sequelae after COVID-19 include fatigue and cognitive impairment. Although symptoms interfere with daily living, the underlying pathology is largely unknown. Previous studies report relative hypometabolism in frontal, limbic and cerebellar regions suggesting focal brain involvement. We aimed to determine whether absolute hypometabolism was present and correlated to same day standardized neurocognitive testing. METHODS: Fourteen patients included from a long COVID clinic had cognitive testing and quantitative dynamic [18F]FDG PET of the brain on the same day to correlate cognitive function to metabolic glucose rate. RESULTS: We found no hypometabolism in frontal, limbic and cerebellar regions in cognitively impaired relative to cognitive intact patients. In contrast, the cognitive impaired patients showed higher cerebellar metabolism (p = 0.03), which correlated with more severe deficits in working memory and executive function (p = 0.03). CONCLUSIONS: Hypermetabolism in the cerebellum may reflect inefficient brain processing and play a role in cognitive impairments after COVID-19.