A muti-modal feature fusion method based on deep learning for predicting immunotherapy response.

Immune checkpoint therapy (ICT) has greatly improved the survival of cancer patients in the past few years, but only a small number of patients respond to ICT. To predict ICT response, we developed a multi-modal feature fusion model based on deep learning (MFMDL). This model utilizes graph neural networks to map gene-gene relationships in gene networks to low dimensional vector spaces, and then fuses biological pathway features and immune cell infiltration features to make robust predictions of ICT. We used five datasets to validate the predictive performance of the MFMDL. These five datasets span multiple types of cancer, including melanoma, lung cancer, and gastric cancer. We found that the prediction performance of multi-modal feature fusion model based on deep learning is superior to other traditional ICT biomarkers, such as ICT targets or tumor microenvironment-associated markers. In addition, we also conducted ablation experiments to demonstrate the necessity of fusing different modal features, which can improve the prediction accuracy of the model.

Geometry Sampling-Based Adaption to DCGAN for 3D Face Generation.

Despite progress in the past decades, 3D shape acquisition techniques are still a threshold for various 3D face-based applications and have therefore attracted extensive research. Moreover, advanced 2D data generation models based on deep networks may not be directly applicable to 3D objects because of the different dimensionality of 2D and 3D data. In this work, we propose two novel sampling methods to represent 3D faces as matrix-like structured data that can better fit deep networks, namely (1) a geometric sampling method for the structured representation of 3D faces based on the intersection of iso-geodesic curves and radial curves, and (2) a depth-like map sampling method using the average depth of grid cells on the front surface. The above sampling methods can bridge the gap between unstructured 3D face models and powerful deep networks for an unsupervised generative 3D face model. In particular, the above approaches can obtain the structured representation of 3D faces, which enables us to adapt the 3D faces to the Deep Convolution Generative Adversarial Network (DCGAN) for 3D face generation to obtain better 3D faces with different expressions. We demonstrated the effectiveness of our generative model by producing a large variety of 3D faces with different expressions using the two novel down-sampling methods mentioned above.

Motion Planning for Convertible Indoor Scene Layout Design.

We present a system for designing indoor scenes with convertible furniture layouts. Such layouts are useful for scenarios where an indoor scene has multiple purposes and requires layout conversion, such as merging multiple small furniture objects into a larger one or changing the locus of the furniture. We aim at planning the motion for the convertible layouts of a scene with the most efficient conversion process. To achieve this, our system first establishes object-level correspondences between the layout of a given source and that of a reference to compute a target layout, where the objects are re-arranged in the source layout with respect to the reference layout. After that, our system initializes the movement paths of objects between the source and target layouts based on various mechanical constraints. A joint space-time optimization is then performed to program a control stream of object translations, rotations, and stops, under which the movements of all objects are efficient and the potential object collisions are avoided. We demonstrate the effectiveness of our system through various design examples of multi-purpose, indoor scenes with convertible layouts.

Real-space navigation testing differentiates between amyloid-positive and -negative aMCI.

OBJECTIVE: To distinguish between patients with amyloid-positive (A+) and -negative (A-) amnestic mild cognitive impairment (aMCI) by simultaneously investigating navigation performance, visual exploration behavior, and brain activations during a real-space navigation paradigm. METHODS: Twenty-one patients with aMCI were grouped into A+ (n = 11) and A- cases by amyloid-PET imaging and amyloid CSF levels and compared to 15 healthy controls. Neuropsychological deficits were quantified by use of the Consortium to Establish a Registry for Alzheimer's Disease-plus cognitive battery. All participants performed a navigation task in which they had to find items in a realistic spatial environment and had to apply egocentric and allocentric route planning strategies. 18F-fluorodeoxyglucose was injected at the start to detect navigation-induced brain activations. Subjects wore a gaze-controlled, head-fixed camera that recorded their visual exploration behavior. RESULTS: A+ patients performed worse during egocentric and allocentric navigation compared to A- patients and controls (p < 0.001). Both aMCI subgroups used fewer shortcuts, moved more slowly, and stayed longer at crossings. Word-list learning, figural learning, and Trail-Making tests did not differ in the A+ and A- subgroups. A+ patients showed a reduced activation of the right hippocampus, retrosplenial, and parietal cortex during navigation compared to A- patients (p < 0.005). CONCLUSIONS: A+ patients with aMCI perform worse than A- patients with aMCI in egocentric and allocentric route planning because of a more widespread impairment of their cerebral navigation network. Navigation testing in real space is a promising approach to identify patients with aMCI with underlying Alzheimer pathology.

In Vivo Imaging of Glial Activation after Unilateral Labyrinthectomy in the Rat: A [18F]GE180-PET Study.

The functional relevance of reactive gliosis for recovery from acute unilateral vestibulopathy is unknown. In the present study, glial activation was visualized in vivo by [18F]GE180-PET in a rat model of unilateral labyrinthectomy (UL) and compared to behavioral vestibular compensation (VC) overtime. 14 Sprague-Dawley rats underwent a UL by transtympanic injection of bupivacaine/arsenilate, 14 rats a SHAM UL (injection of normal saline). Glial activation was depicted with [18F]GE180-PET and ex vivo autoradiography at baseline and 7, 15, 30 days after UL/SHAM UL. Postural asymmetry and nystagmus were registered at 1, 2, 3, 7, 15, 30 days after UL/SHAM UL. Signs of vestibular imbalance were found only after UL, which significantly decreased until days 15 and 30. In parallel, [18F]GE180-PET and ex vivo autoradiography depicted glial activation in the ipsilesional vestibular nerve and nucleus on days 7 and 15 after UL. Correlation analysis revealed a strong negative association of [18F]GE180 uptake in the ipsilesional vestibular nucleus on day 7 with the rate of postural recovery (R = -0.90, p < 0.001), suggesting that glial activation accelerates VC. In conclusion, glial activation takes place in the ipsilesional vestibular nerve and nucleus within the first 30 days after UL in the rat and can be visualized in vivo by [18F]GE180-PET.

Pathological ponto-cerebello-thalamo-cortical activations in primary orthostatic tremor during lying and stance.

Primary orthostatic tremor is a rare neurological disease characterized mainly by a high frequency tremor of the legs while standing. The aim of this study was to identify the common core structures of the oscillatory circuit in orthostatic tremor and how it is modulated by changes of body position. Ten patients with orthostatic tremor and 10 healthy age-matched control subjects underwent a standardized neurological and neuro-ophthalmological examination including electromyographic and posturographic recordings. Task-dependent changes of cerebral glucose metabolism during lying and standing were measured in all subjects by sequential 18F-fluorodeoxyglucose-positron emission tomography on separate days. Results were compared between groups and conditions. All the orthostatic tremor patients, but no control subject, showed the characteristic 13-18 Hz tremor in coherent muscles during standing, which ceased in the supine position. While lying, patients had a significantly increased regional cerebral glucose metabolism in the pontine tegmentum, the posterior cerebellum (including the dentate nuclei), the ventral intermediate and ventral posterolateral nucleus of the thalamus, and the primary motor cortex bilaterally compared to controls. Similar glucose metabolism changes occurred with clinical manifestation of the tremor during standing. The glucose metabolism was relatively decreased in mesiofrontal cortical areas (i.e. the medial prefrontal cortex, supplementary motor area and anterior cingulate cortex) and the bilateral anterior insula in orthostatic tremor patients while lying and standing. The mesiofrontal hypometabolism correlated with increased body sway in posturography. This study confirms and further elucidates ponto-cerebello-thalamo-primary motor cortical activations underlying primary orthostatic tremor, which presented consistently in a group of patients. Compared to other tremor disorders one characteristic feature in orthostatic tremor seems to be the involvement of the pontine tegmentum in the pathophysiology of tremor generation. High frequency oscillatory properties of pontine tegmental neurons have been reported in pathological oscillatory eye movements. It is remarkable that the characteristic activation and deactivation pattern in orthostatic tremor is already present in the supine position without tremor presentation. Multilevel changes of neuronal excitability during upright stance may trigger activation of the orthostatic tremor network. Based on the functional imaging data described in this study, it is hypothesized that a mesiofrontal deactivation is another characteristic feature of orthostatic tremor and plays a pivotal role in development of postural unsteadiness during prolonged standing.

Occupancy of pramipexole (Sifrol) at cerebral dopamine D2/3 receptors in Parkinson's disease patients.

Whereas positron emission tomography (PET) with the antagonist ligand [(18)F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD) patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [(18)F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d.), and again at a later date, after withholding pramipexole 48-72 h (OFF-Sifrol); in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p Ë‚ 0.01) occupancy at [(18)F]fallypride binding sites in globus pallidus (8%) thalamus (9%) and substantia nigra (19%), as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum.

Implementation of the European multicentre database of healthy controls for [(123)I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes.

PURPOSE: Even though [(123)I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS with previously inconclusive findings can be improved by the use of iterative reconstruction algorithms and an improved semiquantitative evaluation which additionally implemented a correction algorithm for patient age and gamma camera dependency (EARL-BRASS; Hermes Medical Solutions, Sweden). METHODS: We identified 101 patients with inconclusive findings who underwent an [(123)I]FP-CIT SPECT between 2003 and 2010 as part of the diagnostic process of suspected PS at the University of Munich, and re-evaluated these scans using iterative reconstruction algorithms and the new corrected EARL-BRASS. Clinical follow-up was obtained in 62 out of the 101 patients and constituted the gold standard for the re-evaluation to assess the possible improvement in diagnostic accuracy. RESULTS: Clinical follow-up confirmed the diagnosis of PS in 11 of the 62 patients. In patients in whom both visual and semiquantitative analysis showed concordant findings (48 patients), a high negative predictive value (93 %), positive predictive value (100 %) and accuracy (94 %) were found, and thus a correct diagnosis was obtained in 45 of the 48 patients. Among the 14 patients with discordant findings, the additional semiquantitative analysis correctly identified all five of nine patients patients without PS by nonpathological semiquantitative findings in visually pathological or inconclusive scans. In contrast, four of the remaining five patients with decreased semiquantitative values but visually normal scans did not show a PS during follow-up. CONCLUSION: The age-corrected and camera-corrected mode of evaluation using EARL-BRASS provided a notable improvement in the diagnostic accuracy of [(123)I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [(123)I]FP-CIT binding due to age-related loss of the dopamine transporter or pathological loss of binding.

Derivation of a respiration trigger signal in small animal list-mode PET based on respiration-induced variations of the ECG signal.

BACKGROUND: Raw PET list-mode data contains motion artifacts causing image blurring and decreased spatial resolution. Unless corrected, this leads to underestimation of the tracer uptake and overestimation of the lesion size, as well as inaccuracies with regard to left ventricular volume and ejection fraction (LVEF), especially in small animal imaging. METHODS AND RESULTS: A respiratory trigger signal from respiration-induced variations in the electro-cardiogram (ECG) was detected. Original and revised list-mode PET data were used for calculation of left ventricular function parameters using both respiratory gating techniques. For adequately triggered datasets we saw no difference in mean respiratory cycle period between the reference standard (RRS) and the ECG-based (ERS) methods (1120 ± 159 ms vs 1120 ± 159 ms; P = n.s.). While the ECG-based method showed somewhat higher signal noise (66 ± 22 ms vs 51 ± 29 ms; P < .001), both respiratory triggering techniques yielded similar estimates for EDV, ESV, LVEF (RRS: 387 ± 56 µL, 162 ± 34 µL, 59 ± 5%; ERS: 389 ± 59 µL, 163 ± 35 µL, 59 ± 4%; P = n.s.). CONCLUSIONS: This study showed that respiratory gating signals can be accurately derived from cardiac trigger information alone, without the additional requirement for dedicated measurement of the respiratory motion in rats.

Anisotropy of Human Horizontal and Vertical Navigation in Real Space: Behavioral and PET Correlates.

Spatial orientation was tested during a horizontal and vertical real navigation task in humans. Video tracking of eye movements was used to analyse the behavioral strategy and combined with simultaneous measurements of brain activation and metabolism ([18F]-FDG-PET). Spatial navigation performance was significantly better during horizontal navigation. Horizontal navigation was predominantly visually and landmark-guided. PET measurements indicated that glucose metabolism increased in the right hippocampus, bilateral retrosplenial cortex, and pontine tegmentum during horizontal navigation. In contrast, vertical navigation was less reliant on visual and landmark information. In PET, vertical navigation activated the bilateral hippocampus and insula. Direct comparison revealed a relative activation in the pontine tegmentum and visual cortical areas during horizontal navigation and in the flocculus, insula, and anterior cingulate cortex during vertical navigation. In conclusion, these data indicate a functional anisotropy of human 3D-navigation in favor of the horizontal plane. There are common brain areas for both forms of navigation (hippocampus) as well as unique areas such as the retrosplenial cortex, visual cortex (horizontal navigation), flocculus, and vestibular multisensory cortex (vertical navigation). Visually guided landmark recognition seems to be more important for horizontal navigation, while distance estimation based on vestibular input might be more relevant for vertical navigation.

Sequential [(18)F]FDG µPET whole-brain imaging of central vestibular compensation: a model of deafferentation-induced brain plasticity.

Unilateral inner ear damage is followed by a rapid behavioural recovery due to central vestibular compensation. In this study, we utilized serial [(18)F]Fluoro-deoxyglucose ([(18)F]FDG)-µPET imaging in the rat to visualize changes in brain glucose metabolism during behavioural recovery after surgical and chemical unilateral labyrinthectomy, to determine the extent and time-course of the involvement of different brain regions in vestibular compensation and test previously described hypotheses of underlying mechanisms. Systematic patterns of relative changes of glucose metabolism (rCGM) were observed during vestibular compensation. A significant asymmetry of rCGM appeared in the vestibular nuclei, vestibulocerebellum, thalamus, multisensory vestibular cortex, hippocampus and amygdala in the acute phase of vestibular imbalance (4 h). This was followed by early vestibular compensation over 1-2 days where rCGM re-balanced between the vestibular nuclei, thalami and temporoparietal cortices and bilateral rCGM increase appeared in the hippocampus and amygdala. Subsequently over 2-7 days, rCGM increased in the ipsilesional spinal trigeminal nucleus and later (7-9 days) rCGM increased in the vestibulocerebellum bilaterally and the hypothalamus and persisted in the hippocampus. These systematic dynamic rCGM patterns during vestibular compensation, were confirmed in a second rat model of chemical unilateral labyrinthectomy by serial [(18)F]FDG-µPET. These findings show that deafferentation-induced plasticity after unilateral labyrinthectomy involves early mechanisms of re-balancing predominantly in the brainstem vestibular nuclei but also in thalamo-cortical and limbic areas, and indicate the contribution of spinocerebellar sensory inputs and vestibulocerebellar adaptation at the later stages of behavioural recovery.

N-acetyl-L-leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus.

An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-µPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]-FDG-µPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of µPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by activating the vestibulocerebellum and deactivating the posterolateral thalamus.

Depressive symptoms accelerate cognitive decline in amyloid-positive MCI patients.

PURPOSE: Late-life depression even in subsyndromal stages is strongly associated with Alzheimer's disease (AD). Furthermore, brain amyloidosis is an early biomarker in subjects who subsequently suffer from AD and can be sensitively detected by amyloid PET. Therefore, we aimed to compare amyloid load and glucose metabolism in subsyndromally depressed subjects with mild cognitive impairment (MCI). METHODS: [(18)F]AV45 PET, [(18)F]FDG PET and MRI were performed in 371 MCI subjects from the Alzheimer's Disease Neuroimaging Initiative Subjects were judged ß-amyloid-positive (Aß+; 206 patients) or ß-amyloid-negative (Aß-; 165 patients) according to [(18)F]AV45 PET. Depressive symptoms were assessed by the Neuropsychiatric Inventory Questionnaire depression item 4. Subjects with depressive symptoms (65 Aß+, 41 Aß-) were compared with their nondepressed counterparts. Conversion rates to AD were analysed (mean follow-up time 21.5 ± 9.1 months) with regard to coexisting depressive symptoms and brain amyloid load. RESULTS: Aß+ depressed subjects showed large clusters with a higher amyloid load in the frontotemporal and insular cortices (p < 0.001) with coincident hypermetabolism (p < 0.001) in the frontal cortices than nondepressed subjects. Faster progression to AD was observed in subjects with depressive symptoms (p < 0.005) and in Aß+ subjects (p < 0.001). Coincident depressive symptoms additionally shortened the conversion time in all Aß+ subjects (p < 0.005) and to a greater extent in those with a high amyloid load (p < 0.001). CONCLUSION: Our results clearly indicate that Aß+ MCI subjects with depressive symptoms have an elevated amyloid load together with relative hypermetabolism of connected brain areas compared with cognitively matched nondepressed individuals. MCI subjects with high amyloid load and coexistent depressive symptoms are at high risk of faster conversion to AD.

The mixed blessing of treating symptoms in acute vestibular failure--evidence from a 4-aminopyridine experiment.

Early symptomatic treatment of acute unilateral vestibulopathy is thought to impede the course of ensuing central vestibular compensation (VC). Despite the great clinical importance of this hypothesis there is no experimental evidence of its validity. The present study addressed this question by investigating the direct effect of 4-aminopyridine (4-AP) on ocular motor and postural symptoms in acute unilateral vestibulopathy as well as its long-term consequences for VC in a rat model of chemical unilateral labyrinthectomy (UL). After UL, one group of Sprague-Dawley rats was treated with 4-AP p.o. (1mg/kg/day), another with 0.9% NaCl solution p.o. for 3days. Behavioural testing for symptoms of vestibular tone imbalance was done 1day before and 1, 2, 3, 5, 7, 9, 15, 21, and 30days after UL. In addition, sequential whole-brain [(18)F]-FDG-µPET was performed before and 1, 3, 7, 15, and 30days after UL to examine and visualize 4-AP-induced modulation of VC. Administration of 4-AP on days 1-3 significantly improved postural imbalance 2h after administration compared to that in controls. This effect was only transient. Remarkably, the 4-AP group had a prolonged and impaired course of postural compensation compared to that of controls. The µPET revealed a significant increase of regional cerebral glucose metabolism (rCGM) in the vestibulocerebellum 2h after administration of 4-AP. However, the 4-AP group exhibited a persistent asymmetry of rCGM after day 3 in the vestibular nuclei and posterolateral thalami. In conclusion, this study confirms the hypothesis that early pharmacological abatement of vestibular symptoms impedes VC.

Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [(18)F]NS14490.

BACKGROUND: The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. Development of applicable highly specific radiotracers has been challenging due to comparably low protein expression. To identify novel ligands as candidates for positron emission tomography (PET), a library of diazabicyclononane compounds was screened regarding affinity and specificity towards α7 nAChRs. From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets. METHODS: Automated radiosynthesis of [(18)F]NS14490 has been performed by [(18)F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [(18)F]NS14490 was consistently approximately 35%, and the total synthesis time was about 90 min. The radiotracer was prepared with >92% radiochemical purity, and the specific activity at the end of the synthesis was 226 ± 68 GBq µmol(-1). PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [(18)F]NS14490 without and with administration of the α7 nAChR partial agonist NS6740 in baseline and blocking conditions. RESULTS: The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g(-1) throughout the telencephalon and was reduced to 2.6 mL g(-1) in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BPND) of approximately 0.5 in the brain of living pigs. In addition, evidence for specific binding in major brain arteries has been obtained. CONCLUSION: [(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.

Extrastriatal binding of [¹²³I]FP-CIT in the thalamus and pons: gender and age dependencies assessed in a European multicentre database of healthy controls.

PURPOSE: Apart from binding to the dopamine transporter (DAT), [(123)I]FP-CIT shows moderate affinity for the serotonin transporter (SERT), allowing imaging of both monoamine transporters in a single imaging session in different brain areas. The aim of this study was to systematically evaluate extrastriatal binding (predominantly due to SERT) and its age and gender dependencies in a large cohort of healthy controls. METHODS: SPECT data from 103 healthy controls with well-defined criteria of normality acquired at 13 different imaging centres were analysed for extrastriatal binding using volumes of interest analysis for the thalamus and the pons. Data were examined for gender and age effects as well as for potential influence of striatal DAT radiotracer binding. RESULTS: Thalamic binding was significantly higher than pons binding. Partial correlations showed an influence of putaminal DAT binding on measured binding in the thalamus but not on the pons. Data showed high interindividual variation in extrastriatal binding. Significant gender effects with 31 % higher binding in women than in men were observed in the thalamus, but not in the pons. An age dependency with a decline per decade (±standard error) of 8.2 ± 1.3 % for the thalamus and 6.8 ± 2.9 % for the pons was shown. CONCLUSION: The potential to evaluate extrastriatal predominant SERT binding in addition to the striatal DAT in a single imaging session was shown using a large database of [(123)I]FP-CIT scans in healthy controls. For both the thalamus and the pons, an age-related decline in radiotracer binding was observed. Gender effects were demonstrated for binding in the thalamus only. As a potential clinical application, the data could be used as a reference to estimate SERT occupancy in addition to nigrostriatal integrity when using [(123)I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors.

Assessment of cerebral dopamine D 2/3 formula-receptors in patients with bilateral vestibular failure.

BACKGROUND: Absence of peripheral vestibular input in bilateral vestibular failure (BVF) has been suggested to induce plastic reorganization in various brain regions. Among several neurotransmitters, dopamine is known to play a key role in cortico-striatal-sensorimotor processing. However, the role of dopamine in vestibular plasticity is scantly documented. OBJECTIVE: Assessment of D 2/3 formula-receptors in patients with BVF. METHODS: D 2/3 formula-receptor-PET using [18F]fallypride and MRI examinations were performed in 12 BVF-patients and 13 healthy controls. RESULTS: BVF-patients showed reduced D 2/3 formula-receptor availability (approximately 40%) in the temporo-parieto-occipital cortex bilaterally, including the multisensory vestibular cortex and visual motion-sensitive areas (MT/MST), as well as in the striatum and the right thalamus. Longer illness duration was associated with bilaterally lower D 2/3 formula-receptor availability in the middle/superior temporal gyrus (GTm/s). D 2/3 formula-receptor availability in the right GTm/s and bilateral insula decreased with severity of symptoms. BVF-patients with oscillopsia showed reduced D 2/3 formula-receptor availability in the right MT/MST and midbrain tectum. CONCLUSIONS: Reduced D 2/3 formula-receptor availability in multisensory vestibular cortical network areas and basal ganglia may indicate a receptor down-regulation due to the lack of peripheral vestibular input. The more pronounced decline in D 2/3 formula-receptor availability in the multisensory vestibular cortex in patients with prolonged illness suggests the occurrence of progressive changes in dopamine transmission.

Erroneous cardiac ECG-gated PET list-mode trigger events can be retrospectively identified and replaced by an offline reprocessing approach: first results in rodents.

The assessment of left ventricular function, wall motion and myocardial viability using electrocardiogram (ECG)-gated [(18)F]-FDG positron emission tomography (PET) is widely accepted in human and in preclinical small animal studies. The nonterminal and noninvasive approach permits repeated in vivo evaluations of the same animal, facilitating the assessment of temporal changes in disease or therapy response. Although well established, gated small animal PET studies can contain erroneous gating information, which may yield to blurred images and false estimation of functional parameters. In this work, we present quantitative and visual quality control (QC) methods to evaluate the accuracy of trigger events in PET list-mode and physiological data. Left ventricular functional analysis is performed to quantify the effect of gating errors on the end-systolic and end-diastolic volumes, and on the ejection fraction (EF). We aim to recover the cardiac functional parameters by the application of the commonly established heart rate filter approach using fixed ranges based on a standardized population. In addition, we propose a fully reprocessing approach which retrospectively replaces the gating information of the PET list-mode file with appropriate list-mode decoding and encoding software. The signal of a simultaneously acquired ECG is processed using standard MATLAB vector functions, which can be individually adapted to reliably detect the R-peaks. Finally, the new trigger events are inserted into the PET list-mode file. A population of 30 mice with various health statuses was analyzed and standard cardiac parameters such as mean heart rate (119 ms ± 11.8 ms) and mean heart rate variability (1.7 ms ± 3.4 ms) derived. These standard parameter ranges were taken into account in the QC methods to select a group of nine optimal gated and a group of eight sub-optimal gated [(18)F]-FDG PET scans of mice from our archive. From the list-mode files of the optimal gated group, we randomly deleted various fractions (5% to 60%) of contained trigger events to generate a corrupted group. The filter approach was capable to correct the corrupted group and yield functional parameters with no significant difference to the optimal gated group. We successfully demonstrated the potential of the fully reprocessing approach by applying it to the sub-optimal group, where the functional parameters were significantly improved after reprocessing (mean EF from 41% ± 16% to 60% ± 13%). When applied to the optimal gated group the fully reprocessing approach did not alter the functional parameters significantly (mean EF from 64% ± 8% to 64 ± 7%). This work presents methods to determine and quantify erroneous gating in small animal gated [(18)F]-FDG PET scans. We demonstrate the importance of a quality check for cardiac triggering contained in PET list-mode data and the benefit of optionally reprocessing the fully recorded physiological information to retrospectively modify or fully replace the cardiac triggering in PET list-mode data. We aim to provide a preliminary guideline of how to proceed in the presence of errors and demonstrate that offline reprocessing by filtering erroneous trigger events and retrospective gating by ECG processing is feasible. Future work will focus on the extension by additional QC methods, which may exploit the amplitude of trigger events and ECG signal by means of pattern recognition. Furthermore, we aim to transfer the proposed QC methods and the fully reprocessing approach to human myocardial PET/CT.

Longitudinal assessment of cerebral ß-amyloid deposition in mice overexpressing Swedish mutant ß-amyloid precursor protein using 18F-florbetaben PET.

UNLABELLED: The progression of ß-amyloid deposition in the brains of mice overexpressing Swedish mutant ß-amyloid precursor protein (APP-Swe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel ß-amyloid tracer (18)F-florbetaben. METHODS: Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of (18)F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BPND) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of ß-amyloid plaque load. RESULTS: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BPND based on the entire dynamic emission recordings. (18)F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P < 0.01) in cortical (18)F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P < 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P < 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R = 0.95, P < 0.001). CONCLUSION: In the first longitudinal PET study in an AD mouse model using the novel ß-amyloid tracer (18)F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.

Effects of acute detoxification of the herbal blend 'Spice Gold' on dopamine D2/3 receptor availability: a [18F]fallypride PET study.

We carried out dynamic [(18)F]fallypride PET scans to measure cerebral dopamine D2/3 receptor availability in a 23-year old patient experiencing a severe withdrawal syndrome upon voluntary abstinence from "Spice", a pre-packaged herbal smoking thought to contain synthetic cannabinoids. Upon admission to the clinic, the patient experienced craving, affective symptoms and a range of somatic complaints, which resolved after several days' monitored abstinence. PET scans were performed on the day of admission, and one week later. Estimates of [(18)F]fallypride binding potential (BPND) were obtained in striatal and extrastriatal brain regions, and compared to results of age-matched healthy control subjects. Upon admission, [(18)F]fallypride BPND was reduced by 20% in the patient's striatum and also in extra-striatal regions. During short-term follow-up upon detoxification, the BPND increased to normal values. This study shows substantial short-term alterations of dopamine D2/3 receptor availability in a patient before and after acute detoxification from "Spice Gold", thus providing first evidence of reversible effects on dopamine receptors of heavy use of a herbal smoking blend.