Hypoxia and tissue destruction in pulmonary TB.

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

Insights into schizophrenia using positron emission tomography: building the evidence and refining the focus.

Schizophrenia involves dysregulation in dopaminergic transmission. Studies show heightened presynaptic striatal dopaminergic function and elevated striatal D(2)/D(3) receptor density in the brain. Cognitive impairments result from hypostimulation of D(1) receptors and are associated with dysfunction in the prefrontal cortex. Here we discuss relevant positron emissions tomography (PET) studies and provide future directions.

Factors affecting the measurement of left ventricular ejection fraction in myocardial perfusion imaging.

BACKGROUND: Estimation of the left ventricular ejection fraction (LVEF) using myocardial perfusion imaging is increasingly used in the evaluation of coronary artery disease. This study aims to compare the effect of (i) two commercially available software packages: quantitative gated single-photon emission computed tomography (SPECT) (QGS) and 4DM-SPECT, and (ii) prereconstruction filtering, on LVEF quantification. METHODS: Images from 101 patients were reconstructed using AutoCardiac and processed using QGS and 4DM-SPECT. Filtering was performed before reconstruction using Hermes FBP SPET on a group of 32 consecutive patients using Butterworth filters (orders 5 and 10; cut-off frequency 0.5-1.2 cycles/cm). RESULTS: Good correlation was observed between QGS and 4DM-SPECT (r=0.88), with an average difference of 2.1%. The difference in LVEF between the two packages ranged from 21 to -28%. The LVEF was overestimated at cut-off frequencies < or = 0.8 cycles/cm compared with higher cut-off frequencies in 26 of 30 (87%) patients. CONCLUSION: There was a clinically significant difference between the LVEF calculated by QGS and 4DM-SPECT and consequently the two packages should not be used interchangeably. The effect of cut-off frequency on LVEF estimation was found to be very patient specific. Changing the cut-off frequency by as little as 0.1 cycles/cm can cause clinically significant differences in LVEF estimation.

Quantitative evaluation of beta-amyloid brain PET imaging in dementia: a comparison between two commercial software packages and the clinical report.

OBJECTIVE: To compare commercially available image analysis tools Hermes BRASS and Siemens Syngo.VIA with clinical assessment in 18F-Florbetapir PET scans. METHODS: 225 scans were reported by clinicians and quantified using two software packages. Scans were classified into Type A (typical features) or non-Type A (atypical features) for both positive and negative scans. For BRASS, scans with z-score ≥ 2 in 2 ≥ region of interest were classed positive. For Syngo.VIA a positive scan was indicated when mean cortical standardized uptake value ratio (mcSUVR) ≥ 1.17. RESULTS: 81% scans were Type A, and 19% scans were non-Type A. The sensitivity of BRASS and Syngo.VIA for Type A scans was 98.8 and 96.3%, specificity was 73 and 92%, respectively. Sensitivity for non-Type A scans was 95.8 and 79.2%, specificity was 36.8 and 57.9%, respectively.A third threshold of identifiable levels of plaque (1.08 ≤ mcSUVR ≤ 1.17) was recommended for Syngo.VIA to increase detection of false negative scans.The false positive rate of BRASS significantly decreased when an alternative positive threshold value of mcSUVR ≥ 1.18.Introduction of alternative criteria did not improve prediction outcome for non-Type A scans. More complex solutions are recommended. CONCLUSION: Hermes criteria for a positive scan leads to a high sensitivity but a low specificity. Siemens Syngo.VIA criteria gives a high sensitivity and specificity and agrees better with the clinical report. Alternative thresholds and classifications may help to improve agreement with the clinical report. ADVANCES IN KNOWLEDGE: Software packages may assist with clinical reporting of more difficult to interpret cases that require a more experienced read.

Clinical 18F-FDG and amyloid brain positron emission tomography/CT in the investigation of cognitive impairment: where are we now?

The number of people living with dementia is increasing, but as yet there remains no cure or disease-modifying treatment. This review aims to help readers understand the role of 18F-FDG PET/CT imaging in the investigation of cognitive impairment and how the advent of amyloid PET/CT imaging may hold the key to radically changing management of the most common form of dementia - Alzheimer's disease. The indications for 18F-FDG PET/CT and amyloid PET/CT imaging in cognitive impairment are outlined. Additionally, the mechanisms of action, technique, patient preparation and acquisition parameters for both are detailed. We conclude by providing a framework for interpreting 18F-FDG PET/CT and amyloid PET/CT imaging in the more common conditions that lead to cognitive impairment conditions with tips on avoiding pitfalls in interpretation.

Optimisation and usefulness of quantitative analysis of 18F-florbetapir PET.

OBJECTIVES: This study investigates the usefulness of quantitative SUVR thresholds on sub types of typical (type A) and atypical (non-type A) positive (Aß+) and negative (Aß-) 18F-florbetapir scans and aims to optimise the thresholds. METHODS: Clinical 18F-florbetapir scans (n = 100) were categorised by sub type and visual reads were performed independently by three trained readers. Inter-reader agreement and reader-to-reference agreement were measured. Optimal SUVR thresholds were derived by ROC analysis and were compared with thresholds derived from a healthy control group and values from published literature. RESULTS: Sub type division of 18F-florbetapir PET scans improves accuracy and agreement of visual reads for type A: accuracy 90%, 96% and 70% and agreement κ > 0.7, κ ≥ 0.85 and -0.1 < κ < 0.9 for all data, type A and non-type A respectively. Sub type division also improves quantitative classification accuracy of type A: optimum mcSUVR thresholds were found to be 1.32, 1.18 and 1.48 with accuracy 86%, 92% and 76% for all data, type A and non-type A respectively. CONCLUSIONS: Aß+/Aß- mcSUVR threshold of 1.18 is suitable for classification of type A studies (sensitivity = 97%, specificity = 88%). Region-wise SUVR thresholds may improve classification accuracy in non-type A studies. Amyloid PET scans should be divided by sub type before quantification. ADVANCES IN KNOWLEDGE: We have derived and validated mcSUVR thresholds for Aß+/Aß- 18F-florbetapir studies. This work demonstrates that division into sub types improves reader accuracy and agreement and quantification accuracy in scans with typical presentation and highlights the atypical presentations not suited to global SUVR quantification.

UK audit of analysis of quantitative parameters from renography data generated using a physical phantom.

BACKGROUND: In this second UK audit of quantitative parameters obtained from renography, phantom simulations were used in cases in which the 'true' values could be estimated, allowing the accuracy of the parameters measured to be assessed. MATERIALS AND METHODS: A renal physical phantom was used to generate a set of three phantom simulations (six kidney functions) acquired on three different gamma camera systems. A total of nine phantom simulations and three real patient studies were distributed to UK hospitals participating in the audit. Centres were asked to provide results for the following parameters: relative function and time-to-peak (whole kidney and cortical region). As with previous audits, a questionnaire collated information on methodology. Errors were assessed as the root mean square deviation from the true value. RESULTS: Sixty-one centres responded to the audit, with some hospitals providing multiple sets of results. Twenty-one centres provided a complete set of parameter measurements. Relative function and time-to-peak showed a reasonable degree of accuracy and precision in most UK centres. The overall average root mean squared deviation of the results for (i) the time-to-peak measurement for the whole kidney and (ii) the relative function measurement from the true value was 7.7 and 4.5%, respectively. These results showed a measure of consistency in the relative function and time-to-peak that was similar to the results reported in a previous renogram audit by our group. CONCLUSION: Analysis of audit data suggests a reasonable degree of accuracy in the quantification of renography function using relative function and time-to-peak measurements. However, it is reasonable to conclude that the objectives of the audit could not be fully realized because of the limitations of the mechanical phantom in providing true values for renal parameters.

An audit of half-count myocardial perfusion imaging using resolution recovery software.

INTRODUCTION: The Nuclear Medicine Software Quality Group of the Institute of Physics and Engineering in Medicine has conducted a multicentre, multivendor audit to evaluate the use of resolution recovery software from several manufacturers when applied to myocardial perfusion data with half the normal counts acquired under a variety of clinical protocols in a range of departments. The objective was to determine whether centres could obtain clinical results with half-count data processed with resolution recovery software that were equivalent to those obtained using their normal protocols. MATERIALS AND METHODS: Sixteen centres selected 50 routine myocardial perfusion studies each, from which the Nuclear Medicine Software Quality Group generated simulated half-count studies using Poisson resampling. These half-count studies were reconstructed using resolution recovery and the clinical reports compared with the original reports from the full-count data. A total of 769 patient studies were processed and compared. RESULTS: Eight centres found only a small number of clinically relevant discrepancies between the two reports, whereas eight had an unacceptably high number of discrepancies. There were no significant differences in acquisition parameters between the two groups, although centres finding a high number of discrepancies were more likely to perform both rest and stress scans on normal studies. CONCLUSION: Half of the participating centres could potentially make use of resolution recovery to reduce the administered activity for myocardial perfusion scans without changing their routine acquisition protocols. The other half could consider adjusting the reconstruction parameters used with their resolution recovery software if they wish to use reduced activity successfully.

An audit of manufacturers' implementation of reconstruction filters in single-photon emission computed tomography.

AIM: The Nuclear Medicine Software Quality Group of the Institute of Physics and Engineering in Medicine has conducted an audit to compare the ways in which different manufacturers implement the filters used in single-photon emission computed tomography. The aim of the audit was to identify differences between manufacturers' implementations of the same filter and to find means for converting parameters between systems. METHODS: Computer-generated data representing projection images of an ideal test object were processed using seven different commercial nuclear medicine systems. Images were reconstructed using filtered back projection and a Butter worth filter with three different cutoff frequencies and three different orders. RESULTS: The audit found large variations between the frequency-response curves of what were ostensibly the same filters on different systems. The differences were greater than could be explained simply by different Butter worth formulae. Measured cutoff frequencies varied between 40 and 180% of that expected. There was also occasional confusion with respect to frequency units. CONCLUSION: The audit concluded that the practical implementation of filtering, such as the size of the kernel, has a profound effect on the results, producing large differences between systems. Nevertheless, this work shows how users can quantify the frequency response of their own systems so that it will be possible to compare two systems in order to find filter parameters on each that produce equivalent results. These findings will also make it easier for users to replicate filters similar to other published results, even if they are using a different computer system.

UK audit of quantification of left-ventricular function using gated myocardial perfusion imaging.

PURPOSE: The aim of the study was to evaluate UK-wide interinstitutional reproducibility of left-ventricular functional parameters, end-systolic volume, end-diastolic volume and ejection fraction, obtained from gated myocardial perfusion imaging (GMPI) studies using technetium-99m-labelled radiopharmaceuticals. The study was carried out by the UK Institute of Physics and Engineering in Medicine Nuclear Medicine Software Quality Group. MATERIALS AND METHODS: Ten anonymized clinical GMPI studies, five with normal perfusion and five with perfusion defects, were made available in DICOM and proprietary formats for download and through manufacturers' representatives. Two of the studies were duplicated in order to assess intraoperator repeatability, giving a total of 12 studies. Studies were made available in 8 and 16 frames/cycle. RESULTS: A total of 58 institutions across England, Scotland, Wales and Northern Ireland participated in this study using six different computer packages. Studies were processed at centres using their normal clinical computers and software. The overall mean±SD ejection fraction for all centres was 58.5±3%; the mean end-diastolic volume was 114±12 ml and the mean end-systolic volume was 54±6 ml. The results were affected by the number of frames per cycle and by the postprocessing computer package, but not by the reconstruction filter in the filtered back-projection. CONCLUSION: Calculation of functional parameters from GMPI using technetium-99m-labelled radiopharmaceuticals is reliable and shows limited variability across the UK.

Automatic classification of 123I-FP-CIT (DaTSCAN) SPECT images.

INTRODUCTION: We present a method of automatic classification of I-fluoropropyl-carbomethoxy-3ß-4-iodophenyltropane (FP-CIT) images. This technique uses singular value decomposition (SVD) to reduce a training set of patient image data into vectors in feature space (D space). The automatic classification techniques use the distribution of the training data in D space to define classification boundaries. Subsequent patients can be mapped into D space, and their classification can be automatically given. METHODS: The technique has been tested using 116 patients for whom the diagnosis of either Parkinsonian syndrome or non-Parkinsonian syndrome has been confirmed from post I-FP-CIT imaging follow-up. The first three components were used to define D space. Two automatic classification tools were used, naïve Bayes (NB) and group prototype. A leave-one-out cross-validation was performed to repeatedly train and test the automatic classification system. Four commercially available systems for the classification were tested using the same clinical database. RESULTS: The proposed technique combining SVD and NB correctly classified 110 of 116 patients (94.8%), with a sensitivity of 93.7% and specificity of 97.3%. The combination of SVD and an automatic classifier performed as well or better than the commercially available systems. CONCLUSION: The combination of data reduction by SVD with automatic classifiers such as NB can provide good diagnostic accuracy and may be a useful adjunct to clinical reporting.

The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia.

Positron emission tomography (PET) offers a strategic imaging platform to provide a map of functional neural correlates associated with the underlying cognitive deficits in schizophrenia. It enables regional cerebral glucose metabolism and dopaminergic and serotonergic receptor function to be studied. PET neuroimaging can therefore be used in drug development and to study putative treatments. Recent PET studies of the first-generation antipsychotics flupentixol and haloperidol, and of the second-generation antipsychotics risperidone, aripiprazole, quetiapine, sertindole, ziprasidone, paliperidone and olanzapine, have been carried out; modulation of limbic circuitry has been found to be a predictor of treatment response. PET can also be used to predict and monitor likely extrapyramidal side effects from antipsychotic treatment. PET and neuropsychological testing can together also allow the study of putative molecular genetic changes associated with schizophrenia. Advances in the imaging, cognition and molecular genetics are likely to lead to the development of future diagnostics, treatments and novel pharmacological agents.

Positron emission tomography in schizophrenia: a new perspective.

UNLABELLED: PET is an important functional imaging technique that can be used to investigate neurotransmitter receptors and transporters directly by mapping human brain function. PET is increasingly being used greatly to advance our understanding of the neurobiology and pathophysiology of schizophrenia. METHODS: This review focuses on the use of PET tracers and kinetic modeling in identifying regional brain abnormalities and regions associated with cognitive functioning in schizophrenia. A variety of PET tracers have been used to identify brain abnormalities, including (11)C, (15)O-water, (18)F-fallypride, and L-3,4-dihydroxy-6-(18)F-fluorophenylalanine ((18)F-FDOPA). RESULTS: Some studies have used compartmental modeling to determine tracer binding kinetics. The most consistent findings show a difference in the dopamine content in the prefrontal cortex, anterior cingulate gyrus, and hippocampus between healthy controls and patients with schizophrenia. Studies also show a higher density of D(2) receptors in the striatum and neural brain dysconnectivity. CONCLUSION: Future investigations integrating clinical, imaging, genetic, and cognitive aspects are warranted to gain a better understanding of the pathophysiology of this disorder.

Selective internal radiation therapy with Yttrium-90 for unresectable liver tumours.

Primary and secondary liver tumours are common malignancies that are being treated more aggressively nowadays than decades ago. Surgery is the most effective method of treatment but is only suitable for a minority of patients with well-defined and easily accessible tumours. Surgical resection is contraindicated in patients with massive involvement of the liver or in cases where the disease involves the confluence of vessels at the porta hepatis. These patients may benefit from a variety of ablative and embolic therapies including selective internal radiation therapy (SIRT) with Yttrium-90 microspheres. SIRT has been introduced in the 1980's but the technology has been refined and made more available only recently. The microspheres are injected directly into the hepatic arteries, through a trans-femoral angiographic approach, and are delivered selectively to tumours due to their preferential blood supply by hepatic arteries. SIRT can therefore target small volumes disease with a higher dose of radiation compared with external-beam radiation and is associated the relatively low toxicity and a good response irrespective of tumor origin. Assessment of response to therapy is best performed with metabolic imaging using (18)F-FDG PET scanning. Although it is not considered as a cure, it has been shown to improve quality of life and prolong survival, with the main cause of death being extra-hepatic spread. The technical and clinical demands of patient selection, treatment planning, administration, and clinical follow-up require an interdisciplinary team willing to work cooperatively to achieve the best result for the patient.