Anita Seese

[18F]Fluoroazomycinarabinofuranoside (18FAZA) and [18F]Fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors

The present study compares the uptake of [(18)F]Fluoroazomycinarabinofuranoside ((18)FAZA), a recently developed hypoxia tracer for PET imaging of tissue hypoxia, with an established tracer [(18)F]Fluoromisonidazole ((18)FMISO) both in vitro, using Walker 256 rat carcinosarcoma cells, and in vivo in experimental rat tumors eleven to twelve days after tumor cell implantation. In vitro studies indicated that hypoxia-selective uptake of both (18)FAZA and (18)FMISO in tumor cells, 20 and 100 minutes post-incubation was of the same magnitude (20 min: 1.24 +/- 0.4% ((18)FAZA); 1.19 +/- 0.7% ((18)FMISO); 100 min: 3.6 +/- 1.6% ((18)FAZA); 3.3 +/- 1.7% ((18)FMISO)). PET imaging reflected a similar radiotracer distribution in rat tumors for (18)FAZA and (18)FMISO one h after radiotracer injection. The concentration of (18)FAZA in the tumors as measured by PET, however, was lower in comparison to (18)FMISO (SUV(FAZA) = 0.61 +/- 0.2 vs. SUV(FMISO) = 0.92 +/- 0.3, p < 0.05) although the tumor to muscle ratios for (18)FAZA and (18)FMISO did not differ in the PET images that were obtained after one h (SUV(FAZA) = 2.5 +/- 0.5 vs. SUV(FMISO) = 2.9 +/- 0.7). A comparison of PET data three h post-injection (SUV(FAZA) = 3.0 +/- 0.5 vs. SUV(FMISO) = 4.6 +/- 1.8, p < 0.05) demonstrated a lower (18)FAZA uptake that indicates a lower sensitivity of (18)FAZA in comparison to (18)FMISO in detecting hypoxic regions at a longer time in this animal model. However, these data also show a faster elimination of (18)FAZA from blood, viscera and muscle tissue, via the renal system. This advantage of a faster reduction of unspecific binding, in light of similar or marginally lower tumor uptake, warrants further investigation of (18)FAZA as a marker of regional hypoxia in tumors.

Attenuation correction by simultaneous emission-transmission myocardial single-photon emission tomography using a technetium-99m-labelled radiotracer : impact on diagnostic accuracy

Irregular photon attenuation may limit the diagnostic accuracy of myocardial single-photon emission tomography (SPET). The aim of this study was to quantify the potential benefit of attenuation correction by simultaneous emission and transmission imaging for the detection of coronary artery disease (CAD) of vessels supplying the inferoposterior wall segments. In 25 male patients with ≥50% stenoses of the right coronary artery and/or circumflex artery but without significant narrowing of the left anterior descending artery, stress studies using technetium-99m tetrofosmin (400 MBq) were carried out with and without attenuation correction. A dual-head camera with L-shaped detector positioning was equipped with two scanning gadolinium-153 line sources. Tomograms were reconstructed and quantified using circumferential count rate profiles of myocardial activity (two in each patient). The profiles were compared with the respective normal ranges obtained from a database of 25 male patients with a <10% likelihood of CAD. In patients without CAD, the maximal differences in count density of different wall segments were reduced from 29.0% in non-corrected (NC) studies to 9.5% in attenuation-corrected (AC) studies. In particular, the inferoposterior and septal wall segments were represented by significantly increased relative count densities after attenuation correction. The effects of attenuation correction proved independent of body mass. In patients with CAD, segmental count densities were abnormal in 84% of the NC studies and 100% of the AC studies. In single-vessel disease the stenotic vessel was identified in 66% of cases by NC studies and in 100% by AC studies. In AC studies, the extent and depth of defects exceeded those in NC studies. For the detection of CAD of the right coronary artery, the receiver operating characteristic (ROC) curves relating to the AC studies demonstrated improved discrimination capacity (P<0.05). ROC analysis of CAD detection yielded normalcy rates of 82% (NC) and 94% (AC) for the circumflex artery and 65% (NC) and 97% (AC) for the right coronary artery area at a sensitivity level of 95%. It is concluded that attenuation correction using the above system may enhance the diagnostic accuracy of myocardial SPET when inferoposterior wall segments are to be evaluated.

Decreased cerebral α4β2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography.

PurposePostmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer’s disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4β2* nicotinic acetylcholine receptor (α4β2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD.MethodsNine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BPND) of 2-[18F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis.ResultsBoth patients with AD and MCI showed a significant reduction in 2-[18F]FA-85380 BPND in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[18F]FA-85380 BPND correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[18F]FA-85380 BPND.Conclusion2-[18F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4β2* nAChRs which seems to be an early event in AD. In addition, 2-[18F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.

PET Quantification of 18F-Florbetaben Binding to β-Amyloid Deposits in Human Brains

18F-florbetaben is a novel 18F-labeled tracer for PET imaging of β-amyloid deposits in the human brain. We evaluated the kinetic model–based approaches to the quantification of β-amyloid binding in the brain from dynamic PET data. The validity of the practically useful tissue ratio was also evaluated against the model-based parameters. Methods: 18F-florbetaben PET imaging was performed with concurrent multiple arterial sampling after tracer injection (300 MBq) in 10 Alzheimer disease (AD) patients and 10 age-matched healthy controls. Regional brain-tissue time–activity curves for 90 min were analyzed by a 1-tissue-compartment model and a 2-tissue-compartment model (2TCM) with metabolite-corrected plasma data estimating the specific distribution volume (VS) and distribution volume ratio (DVR [2TCM]) and a multilinear reference tissue model estimating DVR (DVR [MRTM]) using the cerebellar cortex as the reference tissue. Target–to–reference tissue standardized uptake value ratios (SUVRs) at 70–90 min were also calculated. Results: All brain regions required 2TCM to describe the time–activity curves. All β-amyloid binding parameters in the cerebral cortex (VS, DVR [2TCM], DVR [MRTM], and SUVR) were significantly increased in AD patients (P < 0.05), and there were significant linear correlations among these parameters (r2 > 0.83). Effect sizes in group discrimination between 8 β-amyloid–positive AD scans and 9 β-amyloid–negative healthy control scans for all binding parameters were excellent, being largest for DVR (2TCM) (4.22) and smallest for VS (3.25) and intermediate and the same for DVR (MRTM) and SUVR (4.03). Conclusion: These results suggest that compartment kinetic model–based quantification of β-amyloid binding from 18F-florbetaben PET data is feasible and that all β-amyloid binding parameters including SUVR are excellent in discriminating between β-amyloid–positive and –negative scans.

Calibration of gamma camera systems for a multicentre European 123I-FP-CIT SPECT normal database

PurposeA joint initiative of the European Association of Nuclear Medicine (EANM) Neuroimaging Committee and EANM Research Ltd. aimed to generate a European database of [123I]FP-CIT single photon emission computed tomography (SPECT) scans of healthy controls. This study describes the characterization and harmonization of the imaging equipment of the institutions involved.Methods123I SPECT images of a striatal phantom filled with striatal to background ratios between 10:1 and 1:1 were acquired on all the gamma cameras with absolute ratios measured from aliquots. The images were reconstructed by a core lab using ordered subset expectation maximization (OSEM) without corrections (NC), with attenuation correction only (AC) and additional scatter and septal penetration correction (ACSC) using the triple energy window method. A quantitative parameter, the simulated specific binding ratio (sSBR), was measured using the “Southampton” methodology that accounts for the partial volume effect and compared against the actual values obtained from the aliquots. Camera-specific recovery coefficients were derived from linear regression and the error of the measurements was evaluated using the coefficient of variation (COV).ResultsThe relationship between measured and actual sSBRs was linear across all systems. Variability was observed between different manufacturers and, to a lesser extent, between cameras of the same type. The NC and AC measurements were found to underestimate systematically the actual sSBRs, while the ACSC measurements resulted in recovery coefficients close to 100% for all cameras (AC range 69–89%, ACSC range 87–116%). The COV improved from 46% (NC) to 32% (AC) and to 14% (ACSC) (p < 0.001).ConclusionA satisfactory linear response was observed across all cameras. Quantitative measurements depend upon the characteristics of the SPECT systems and their calibration is a necessary prerequisite for data pooling. Together with accounting for partial volume, the correction for scatter and septal penetration is essential for accurate quantification.

Is correction for age necessary in neuroimaging studies of the central serotonin transporter

The central neurotransmitter serotonin plays a major role in a number of neuropsychiatric disorders. However, results from post-mortem and in vivo neuroimaging studies of the influence of age on the number of presynaptic serotonin transporters (SERT) are controversial. To provide further evidence of relevance for this ongoing discussion, SERT were imaged in 22 persons without neuropsychiatric impairment using [123I]2β-carbomethoxy-3β-(iodophenyl)tropane ([123I]β-CIT) and high-resolution single-photon emission tomography (SPET). The SPET analysis method was based on magnetic resonance image co-registration in order to quantify SERT with acceptable inter- and intra-observer variability. Using this technique, we found a significant age-related decline in the thalamic/hypothalamic and midbrain/upper brainstem SERT density, which was more pronounced than that previously reported in the literature. From these results we conclude that age-related changes in SERT density need to be considered in future clinical studies.

Proposal for the standardisation of multi-centre trials in nuclear medicine imaging: prerequisites for a European 123I-FP-CIT SPECT database.

PurposeMulti-centre trials are an important part of proving the efficacy of procedures, drugs and interventions. Imaging components in such trials are becoming increasingly common; however, without sufficient control measures the usefulness of these data can be compromised. This paper describes a framework for performing high-quality multi-centre trials with single photon emission computed tomography (SPECT), using a pan-European initiative to acquire a normal control dopamine transporter brain scan database as an example.MethodsA framework to produce high-quality and consistent SPECT imaging data was based on three key areas: quality assurance, the imaging protocol and system characterisation. Quality assurance was important to ensure that the quality of the equipment and local techniques was good and consistently high; system characterisation helped understand and where possible match the performance of the systems involved, whereas the imaging protocol was designed to allow a degree of flexibility to best match the characteristics of each imaging device.ResultsA total of 24 cameras on 15 sites from 8 different manufacturers were evaluated for inclusion in our multi-centre initiative. All results matched the required level of specification and each had their performance characterised. Differences in performance were found between different system types and cameras of the same type. Imaging protocols for each site were modified to match their individual characteristics to produce comparable high-quality SPECT images.ConclusionA framework has been designed to produce high-quality data for multi-centre SPECT studies. This framework has been successfully applied to a pan-European initiative to acquire a healthy control dopamine transporter image database.

Dissociating behavioral disorders in early dementia - An FDG-PET study

Behavioral impairments occur frequently in dementia. Studies with magnetic resonance imaging, measuring atrophy, have systematically investigated their neural correlates. Such a systematic approach has not yet been applied to imaging with [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET), although regional hypometabolism may precede and exceed atrophy in dementia. The present study related all behavioral disorders as assessed with the Neuropsychiatric Inventory to reductions in brain glucose utilization as measured by FDG-PET with Statistical Parametric Mapping (SPM5). It included 54 subjects mainly with early Alzheimers disease, frontotemporal lobar degeneration, and subjective cognitive impairment. Apathy, disinhibition and eating disorders - most frequent in frontotemporal lobar degeneration - correlated significantly with regional brain hypometabolism. Whereas a single regressor analysis and conjunction analysis revealed largely overlapping frontomedian regions that were associated with all three behavioral domains, a disjunction analysis identified three specific neural networks for each behavioral disorder, independent of dementia severity. Apathy was related to the ventral tegmental area, a component of the motivational dopaminergic network; disinhibition to both anterior temporal lobes including the anterior hippocampi and left amygdala, caudate head, orbitofrontal cortex and insulae; and eating disorders to the right lateral (orbito) frontal cortex/insula. Our study contributes to the understanding of behavioral deficits in early dementia and suggests specific diagnostic and therapeutic approaches.

Executive and behavioral deficits share common neural substrates in frontotemporal lobar degeneration — A pilot FDG-PET study

Behavioral and executive dysfunctions are typical symptoms of frontotemporal lobar degeneration, associated with its subtypes frontotemporal and semantic dementia. Although both functions depend on the frontal lobes, no study has yet compared their neural correlates in frontotemporal lobar degeneration. Accordingly, we correlated clinical scores of behavioral and executive deficits with glucose utilization as measured by [(18)F]fluorodeoxyglucose positron emission tomography in 17 patients with frontotemporal lobar degeneration and 9 age- and sex-matched control subjects. Impairment in executive functions was measured by the Behavioral Assessment of the Dysexecutive Syndrome, a modified Stroop paradigm and/or the Tower of Toronto Test. Behavioral deficits were examined with the Neuropsychiatric Inventory. Executive dysfunction was correlated with diminished glucose utilization in frontomedial and frontolateral cortices. Brain regions included the anterior cingulate and midcingulate gyri, anterior medial frontal cortex, and left frontolateral cortex. Behavioral deficits were associated with mainly frontomedial networks, particularly the anterior medial frontal cortex, gyrus rectus, and area subcallosa. Our pilot study reveals partially overlapping neural correlates of executive and behavioral dysfunction in frontotemporal lobar degeneration. The results suggest that some behavioral deficits, namely disinhibition and appetite and eating abnormalities, are particularly related to executive dysfunction. This hypothesis might be further explored in studies involving larger patient groups.

Changes in local cerebral blood flow by neuroactivation and vasoactivation in patients with impaired cognitive function

Imaging of local cerebral blood flow (ICBF) may serve as an important supplementary tool in the aetiological assessment of dementias. In early or preclinical disease, however, there are less characteristic changes in ICBF. In the present study it was investigated whether vasoactivation or neuroactivation may produce more pronounced local ICBF deficits. Local CBF was investigated by using technetium-99m hexamethylpropylene amine oxime and single-photon emission tomography (SPET) in 80 patients (50 with mild cognitive impairment and 30 with dementia of Alzheimer type (DAT), all without evidence of cerebrovascular disease) at rest (baseline) and during activation. In 31 studies patients underwent vasomotor activation with acetazolamide, while 62 studies were performed under cognitive challenge (neuroactivation by labyrinth task). Cortical activity relative to that of cerebellum increased significantly in a right temporal region and tended to increase in other cortical regions upon vasoactivation. In contrast, neuroactivation reduced cortical activity relative to that of cerebellum in several left and right temporal and in left parietal regions. Visual classification of SPET images of patients with probable DAT by three observers resulted in a reduction of the number of definitely abnormal patterns from 9/12 to 4/12 by vasoactivation and an increase from 10/18 to 15/18 by neuroactivation. Correspondingly, abnormal ratings in patients with mild cognitive dysfunction were reduced from 7/19 to 5/19 by vasoactivation and were increased from 12/2I to 18/21 by neuroactivation. In conclusion, vasoactivation does not enhance local relative perfusion deficits in patients with cognitive impairment of non-vascular aetiology, whereas neuroactivation by labyrinth task produces more pronounced local flow differences and enhances abnormal patterns in ICBF imaging.