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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.

Interactive techniques in Virtual Reality (VR) is rapidly developing in the recent years. However, the consistency of the interaction activities in VR and real-world remains a subject to be further studied. In this work, we study the consistency of casting action between VR and real-world. In our experiments, we let participants cast a ball to a walking human virtual agent, which is driven by a motion capture system in the virtual environment. By comparing to the casting accuracy in real-world, we found that the participants' performance under various of the experimental configurations is consistently reduced in VR. We also found that the moving ‘speed’ factor of the casting target barely affected the accuracy in VR, which was different in the real-world environment. This study will provide an important experimental reference to develop future VR systems based on casting actions.

Background The free-fatty acid receptor-1 (FFA-1) is expressed by β-cells and is a promising target for molecular imaging of functional β-cell mass. Recently, the ((3-[18F]fluoropropyl)sulfonyl)propoxy-derivative of the high-affinity FFA-1 agonist TAK-875 ([ 18 F]7) was reported. Here we describe the preparation of this tracer in high molar activity using a purification method permitting separation of [ 18 F]7 from a structurally-related by-product and evaluation of the tracer in rats as a potential FFA-1 PET imaging agent. Results The radiotracer was produced by nucleophilic radio-fluorination of the tosylate precursor and deprotection of the methyl ester. Semi-preparative HPLC with a C18 column revealed that [ 18 F]7 co-eluted with a non-radioactive impurity. Mass spectrometry identified the impurity as the alkene-containing elimination by-product. A pentafluorophenyl-functionalized HPLC column was found to separate the two compounds and allowed for purification of [ 18 F]7 in high molar activity. A strong anion-exchange resin was used to reformulate [ 18 F]7 in high concentration. Starting from 96 to 311 GBq of [18F]fluoride, 3.8–15.4 GBq of pure [ 18 F]7 (end of synthesis (EOS)) was prepared (RCY 8.3% ± 1.1% decay-corrected, n = 4) in high molar activity (166–767 GBq/μmol at EOS). This PET agent was evaluated in rats using dynamic microPET/CT imaging, ex vivo biodistribution, and radio-metabolite studies. MicroPET/CT exhibited high uptake of the tracer in the abdominal area. There was no measurable decrease of the PET signal in the pancreatic area in rats pre-treated with saturating doses (30 mg/kg) of TAK-875. Biodistribution studies corroborated the microPET/CT results. Radiometabolism analyses revealed high compound stability with only the parent molecule detected in the pancreas. Conclusions Analysis of the crude reaction mixture and identification of the elimination by-product allowed for the development of a fully automated process to prepare the TAK-875-derived PET agent [ 18 F]7 in high purity and high molar activity. Even though the radiotracer exhibited high in vivo stability, microPET/CT and biodistribution results confirmed recent reports demonstrating that lipophilic analogs of TAK-875 display a high degree of non-specific binding, masking any specific binding to FFA-1 in pancreatic β-cells. Future development of TAK-875-derived PET tracers should focus on reducing non-specific binding in the pancreatic tissue.

Whereas positron emission tomography (PET) with the antagonist ligand [18F]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 [18F]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 ˂ 0.01) occupancy at [18F]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., Graphical abstract Mean parametric maps of the binding potential (BPND) of [18F]fallypride in the coronal plan of a group of nine patients with Parkinson's disease, investigated after withdrawal from Sifrol (pramipexole) and during treatment as usual, showing substantial occupancy at dopamine D2/3 receptors in the substantia nigra, but no difference in the tail of the caudate nucleus.Image 1, Highlights • Fallypride PET recordings in nine PD patients, scanned on- and off medication with pramipexole • No occupancy in the striatum, despite improved motor symptoms • Substantial occupancy in substantia nigra, thalamus and globus pallidus

[object Object]Purpose Even though [123I]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 [123I]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 [123I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [123I]FP-CIT binding due to agerelated loss of the dopamine transporter or pathological loss of binding.

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).[(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 β-amyloid-positive (Aβ+; 206 patients) or β-amyloid-negative (Aβ-; 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 Aβ+, 41 Aβ-) 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.Aβ+ 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 Aβ+ subjects (p 0.001). Coincident depressive symptoms additionally shortened the conversion time in all Aβ+ subjects (p 0.005) and to a greater extent in those with a high amyloid load (p 0.001).Our results clearly indicate that Aβ+ 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.

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.

Objective: To determine pathologic regulations and potential compensatory mechanisms in the supraspinal locomotor network of patients with progressive supranuclear palsy (PSP) by investigation of brain activation during walking and correlation to gait performance. Methods: Twelve patients with PSP were scanned with [ 18 F]-FDG-PET during walking and at rest as has been described earlier. Results were compared to age-matched healthy controls (n = 12). Results: The major results were as follows. 1) At rest, the regional cerebral glucose metabolism (rCGM) in the supraspinal locomotor centers, i.e., the prefrontal cortex, the subthalamic nucleus, and the pedunculopontine/cuneiform nucleus complex, was reduced in PSP. 2) Severity of gait impairment, measured by gait velocity, step length, and progressive supranuclear palsy rating scales/gait, correlated with decrease of rCGM in the prefrontal cortex and subthalamic nucleus. 3) Accordingly, during walking functional activation of the prefrontal cortex, the subthalamic nucleus, the pedunculopontine/cuneiform nucleus complex, and the thalamus was reduced in patients with PSP compared to controls. 4) The precentral gyrus and the vermal cerebellum were activated more strongly during locomotion in PSP. Conclusions: Gait impairment in PSP is especially associated with dysfunction of the indirect, modulatory prefrontal–subthalamic–pedunculopontine loop of locomotor control. The direct, stereotyped locomotor loop from the primary motor cortex to the spinal cord with rhythmic cerebellar drive shows increased activity in PSP. The latter can be interpreted as an attempt of compensation, but may also contribute to a stereotyped gait pattern in PSP.

Positron emission tomography (PET) with the high affinity dopamine D2/3 receptor ligand [18F]-fallypride affords estimates of the binding potential (BPND) in extra-striatal regions of low receptor abundance, but the sufficient recording time for accurate measurements in striatum has been called into question. We have earlier argued that transient equilibrium measurements are obtained in striatum with [18F]-fallypride PET recordings of 3 h duration, which may be the practical limit for clinical investigations without interrupted scanning. However, the high extraction fraction of [18F]-fallypride predicts flow-dependence of tracer delivery to brain, which may be a source of variance of the apparent BPND in regions of high binding. To test this prediction, we conducted a retrospective analysis of [18F]-fallypride PET data from a group of 50 healthy volunteers (age 18–58 years [mean ± SD: 32.6 ± 10.6), who had participated in clinical studies without arterial input measurements. We used the initial 120-s integral (AUC) of the venous confluence (VC) as a surrogate marker for cerebral blood flow (CBF) and tested for correlations between regional estimates of BPND calculated by the simplified reference tissue model (SRTM) and the individual VC-AUC. The magnitude of BPND in a high binding region (putamen), but not in a low binding region (thalamus) correlated positively with VC-AUC, suggesting that approximately 9% of the variance in the [18F]-fallypride BPND in putamen can be attributed to individual differences in this surrogate marker for CBF, a contribution equal in magnitude to the effects of age on BPND in putamen of the present healthy control group. Synapse, 2013. © 2012 Wiley Periodicals, Inc.

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.

Absolute quantitation of the cerebral metabolic rate for glucose (CMRglc) can be obtained in positron emission tomography (PET) studies when serial measurements of the arterial [(18)F]-fluoro-deoxyglucose (FDG) input are available. Since this is not always practical in PET studies of rodents, there has been considerable interest in defining an image-derived input function (IDIF) by placing a volume of interest (VOI) within the left ventricle of the heart. However, spill-in arising from trapping of FDG in the myocardium often leads to progressive contamination of the IDIF, which propagates to underestimation of the magnitude of CMRglc. We therefore developed a novel, non-invasive method for correcting the IDIF without scaling to a blood sample. To this end, we first obtained serial arterial samples and dynamic FDG-PET data of the head and heart in a group of eight anaesthetized rats. We fitted a bi-exponential function to the serial measurements of the IDIF, and then used the linear graphical Gjedde-Patlak method to describe the accumulation in myocardium. We next estimated the magnitude of myocardial spill-in reaching the left ventricle VOI by assuming a Gaussian point-spread function, and corrected the measured IDIF for this estimated spill-in. Finally, we calculated parametric maps of CMRglc using the corrected IDIF, and for the sake of comparison, relative to serial blood sampling from the femoral artery. The uncorrected IDIF resulted in 20% underestimation of the magnitude of CMRglc relative to the gold standard arterial input method. However, there was no bias with the corrected IDIF, which was robust to the variable extent of myocardial tracer uptake, such that there was a very high correlation between individual CMRglc measurements using the corrected IDIF with gold-standard arterial input results. Based on simulation, we furthermore find that electrocardiogram-gating, i.e. ECG-gating is not necessary for IDIF quantitation using our approach.

Standing, walking, and running are sensorimotor tasks that develop during childhood. Thereafter they function automatically as a result of a supraspinal network that controls spinal pattern generators. The present study used functional magnetic resonance imaging (fMRI) to investigate age-dependent changes in the supraspinal locomotor and postural network of normal subjects during mental imagery of locomotion and stance. Sixty healthy subjects (ages: 24–78 years), who had undergone a complete neurological, neuro-ophthalmological, and sensory examination to rule out disorders of balance and gait, were trained for the conditions lying, standing, walking, and running in order to imagine these conditions on command in 20-second sequences with the eyes closed while lying supine in an magnetic resonance imaging (MRI) scanner. The following blood oxygen level-dependent (BOLD) signal changes during locomotion and stance were found to be independent of age: (1) prominent activations in the supplementary motor areas, the caudate nuclei, visual cortical areas, vermal, and paravermal cerebellum; (2) significant deactivations in the multisensory vestibular cortical areas (posterior insula, parietoinsular vestibular gyrus, superior temporal gyrus), and the anterior cingulate during locomotion. The following differences in brain activation during locomotion and stance were age-dependent: relative increases in the cortical BOLD signals in the multisensory vestibular cortices, motion-sensitive visual cortices (MT/V5), and somatosensory cortices (right postcentral gyrus). In advanced age this multisensory activation was most prominent during standing, less during walking, and least during running. In conclusion, the functional activation of the basic locomotor and postural network, which includes the prefrontal cortex, basal ganglia, brainstem, and cerebellar locomotor centers, is preserved in the elderly. Two major age-dependent aspects of brain activation during locomotion and stance were found: the mechanism of cortical inhibitory reciprocal interaction between sensory systems during locomotion and stance declines in advanced age; and consequently, multisensory cortical control of locomotion and stance increases with age. These findings may indicate a more conscious locomotor and postural strategy in the elderly.

Positron emission tomography (PET) shows reduced binding of the dopamine D2/3 antagonist [11C]raclopride in striatum of withdrawn psychostimulant abusers, but not consistently in patients with alcohol dependence (AD). We make first use of the high affinity ligand [18F]fallypride to obtain serial measures of D2/3 receptor availability in striatal and extrastriatal regions of AD patients undergoing detoxification. Seventeen patients (mean age 44±5y) with AD and 14 age-matched healthy volunteers participated. Each patient underwent [18F]fallypride PET upon hospital admission, and again 1-2 weeks later; two patients achieving abstinence, and two with substantial harm reduction had additional PET follow-up at 1 year. Dynamic 180-minute PET recordings were used for volume of interest (VOI)-based and voxel-wise analysis of [18F]fallypride binding potential (BPND). Mean baseline BPND in striatum of the AD patients (15.7±3.6) was unaltered during short-term follow-up, and did not differ from that in healthy controls (16.8±3.0); however, BPND was 10-20% lower in thalamus, hippocampus, and insular and temporal cortex of the AD patients (P

To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [18F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [18F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg·kg−1 bolus + 1 mg·kg−1·h−1 continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time–radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [18F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUVmax was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUVmax 1.53 ± 0.32). Administration of NS6740 significantly decreased [18F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BPND. The baseline BPND ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BPND in regions with high [18F]NS10743 binding (temporal lobe −29%, p = 0.01; midbrain: −35%, p = 0.02), without significantly altering the BPND in low binding regions (cerebellum: −16%, p = 0.2). This study confirms the potential of [18F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET.

The relationship between the photon beam quality specifier % d d ( 10 ) x and the Spencer–Attix water to air restricted mass collision stopping-power ratio, ( L ¯ ∕ ρ ) air water , is studied using Monte Carlo simulation with realistic beams in contrast to the previously used realistic but uniform spectra from an isotropic point source. The differences between accelerators with and without flattening filters are investigated since flattening filter free accelerators appear to be useful for IMRT. Our results show that the standard relationship between % d d ( 10 ) x and ( L ¯ ∕ ρ ) air water , which is used in the TG–51 protocol to calculate the quality conversion factor k Q , is acceptable for beams with or without a flattening filter with a maximum error of 0.4%, although a fit to the new data would reduce the maximum error to 0.2%. Reasons for differences between the individual values of % d d ( 10 ) x and ( L ¯ ∕ ρ ) air water with and without a flattening filter are studied. Specifically the differences due to the softening of the beam, the change in shape of the profile, and the inclusion of radial variations in the photon energy spectra, are investigated. It is shown that if TPR 10 20 is used as a beam quality specifier, there are two different relationships between TPR 10 20 and ( L ¯ ∕ ρ ) air water which differ by 0.4%–1%. When using TPR 10 20 as a beam quality specifier in a beam without a flattening filter, one should subtract 0.5% from the value of k Q for a given value of TPR 10 20 .

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.

Background Functional imaging studies on the central vestibular system by fMRI and H 2 15 O-PET in healthy volunteers revealed similarities and differences in cortical activation patterns ( Bense, 2001 , Dietrich, 2003 , Stephan, 2005 , Stephan, 2009 , Becker-Bense, 2014 ). These are ascribed to different experimental procedures and techniques. Whereas PET maps cerebral blood flow, fMRI measures changes of blood oxygenation via magnetic susceptibility changes.Galvanic vestibular stimulation (GVS) is applicable inside PET and MRI; it induces a perception of apparent self-motion mainly at onset ( Stephan, 2009 ). Aim of the current study was to design a protocol for simultaneous PET-MRI of the vestibular system in order to compare the activation patterns between the two methods providing additional information for a deeper insight into the different mechanisms and improve the interpretation of the data. Methods Six simultaneous PET-MRI scans were acquired in a hybrid scanner in nine healthy volunteers. During the stimulation scans AC-GVS was applied at 1 Hz ( Stephan, 2005 ) with eyes closed ( Fig. 1 ). FMRI EPI sequences were measured over 260 s. Dynamic PET acquisition started with injection of 750 MBq H 2 15 O in a semibolus technique simultaneously with fMRI. Statistical direct comparison of PET and fMRI data were performed (paired t-test, SPM8). Results MRI: Onset-related activation was seen of the multisensory vestibular cortical network and ocular motor areas bilaterally, as well as of premotor area BA 6 (SMA). Block-related activation represented a subset of this activation pattern without SMA activation. PET: The PET data of the first stimulation blocks revealed prominent activation of the SMA and cerebellar vermis. MRI vs PET: Paired comparison showed significantly stronger SMA PET signals compared to block-related MRI that was not present for onset-related MRI. Conclusions The proposed procedure is suitable for direct statistical comparison of H 2 15 O-PET and fMRI activations during vestibular stimulation. At comparable spatial resolution, the higher temporal resolution of fMRI can be utilized to interpret the simultaneous PET data in another context. On the other hand, the quantitative nature of the PET data can augment the fMRI data that provide only an indirect measure of cortical processing. The most different effects were seen in the SMA, where the PET signal seems to reflect the onset-related MRI signal due to self-motion perception which is most prominent at stimulus onset causing a preparatory motor response.

Here, we report a 100 ns molecular dynamics simulation of the folding process of a recently designed autonomous-folding mini-protein designated as tc5b with a new AMBER force field parameter set developed based on condensed-phase quantum mechanical calculations and a Generalized Born continuum solvent model. Starting from its fully extended conformation, our simulation has produced a final structure resembling that of NMR native structure to within 1 A main-chain root mean square deviation. Remarkably, the simulated structure stayed in the native state for most part of the simulation after it reached the state. Of greater significance is that our simulation has not only reached the correct main-chain conformation, but also a very high degree of accuracy in side-chain packing conformation. This feat has traditionally been a challenge for ab initio simulation studies. In addition to characterization of the trajectory, comparison of our results to experimental data is also presented. Analysis of the trajectory suggests that the rate-limiting step of folding of this mini-protein is the packing of the Trp side-chain.

Objective Reactive gliosis may improve recovery after acute unilateral vestibulopathy (AUV). In the present study glial activation was visualized in vivo by [ 18 F]GE180-PET in a rat model of unilateral labyrinthectomy (UL) and compared to behavioural vestibular compensation (VC) over time. Methods 14 Sprague-Dawley rats underwent a left-sided UL by a transtympanic injection of bupivacaine and arsenilate, 14 rats received a left-sided middle-ear sham injection of 0.9% NaCl-solution as a control group (SHAM-UL). For functional imaging of glial activation, PET with [ 18 F]GE180, a novel translocator protein (TSPO) ligand, was performed at baseline and 7, 15, 30 days after UL/SHAM-UL. Ex vivo autoradiography was done at the respective time points for high resolution validation of PET and combined with Nissl-staining of the corresponding slices for detailed anatomic mapping. Established behavioural testing for symptoms of vestibular tone imbalance including registration of postural asymmetry and nystagmus was performed at baseline and at days 1, 2, 3, 7, 15, 30 after UL/SHAM-UL. Results Only after UL rats showed clinical signs of vestibular imbalance which significantly decreased until days 15 and 30. In parallel, [ 18 F]GE180-PET and ex vivo autoradiography depicted glial activation in the ipsilesional vestibular nerve and nucleus at days 7 and 15 after UL. Correlation analysis revealed a strong negative association of [ 18 F]GE180 uptake in the ipsilesional vestibular nucleus at day 7 with the rate of postural recovery (R = −0.90, p 18 F]GE180 binding in the ipsilesional vestibular nerve and nucleus 7 days after symptom onset. Interpretation In the rat glial activation takes place in the ipsilesional vestibular nerve and nucleus within the first 30 days after UL and can be visualized in vivo by [ 18 F]GE180-PET. Comparative analysis of behavioural and [ 18 F]GE180-PET data proves that glial activation is beneficial for VC. In human AUV neuroinflammation seems to analogously appear in the ipsilesional vestibular nerve and nucleus.

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. 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

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.

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, [18F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [18F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets. Methods Automated radiosynthesis of [18F]NS14490 has been performed by [18F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [18F]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 [18F]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 [18F]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.

Altered SERT and DAT availabilities during treatment with escitalopram were investigated with [(123)I]2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) SPECT in a series of patients fulfilling the criteria for unipolar major depressive disorder (MDD). 27 patients (10m, 42±16y) with diagnosis of MDD were recruited for the study. All patients underwent neuropsychiatric testing for assessment of Hamilton Depression (HAM-D) and Beck Depression Inventory (BDI) scores. At baseline, [(123)I]β-CIT SPECT recordings were acquired 4h (SERT-weighted) and 20-24h p.i (DAT-weighted). Follow-up scans and neuropsychiatric testing were performed after six weeks of stable escitalopram medication. Voxel-wise parametric maps of specific/ non-specific ratios-1 (~BPND) were calculated. At baseline, DAT-weighted BPND was 5.06±0.81 in striatum and SERT-weighted BPND was 0.94±0.18 in thalamus. There were significant negative correlations with age for DAT in striatum (R=-0.60; p

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.

Purpose Apart from binding to the dopamine transporter (DAT), [123I]FP-CITshows 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 welldefined 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 [123I]FPCIT 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 [123I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors.

Background and aim Reactive gliosis may be beneficial for central compensation after unilateral inner ear damage. The aim of the present study was to visualize whole brain glial activation in vivo and over time by serial [ 18 F]-GE180- μ PET in a rat model of chemical unilateral labyrinthectomy (UL). Methods Ten Sprague–Dawley rats underwent a left-sided UL by transtympanic injection of bupivacaine and arsenilate, ten rats received a left-sided middle-ear injection of saline as a control group. Behavioural testing for symptoms of vestibular tone imbalance including registration of nystagmus and postural asymmetry was performed 1 day before and at days 1, 3, 7, 15, 30 after UL/sham injection. For functional imaging of glial activation, whole-brain μ PET with [ 18 F]-GE180, a novel translocator protein (tspo) ligand, was performed before and on 7, 15, 30 days after UL/sham injection. In vivo autoradiography was done at the respective time points for crosscheck and combined with Nissl-staining of the corresponding slices for detailed anatomic mapping. Results All rats showed clinical signs of an acute vestibular syndrome following UL with a maximum at 2 and 3 days. Nystagmus disappeared until day 5, postural asymmetry decreased significantly until day 15. In the UL group, [ 18 F]-GE180- μ PET depicted a glial activation in the ipsilesional vestibular, cochlear and facial nucleus at day 7, which further increased until day 15 and was only slightly visible at day 30. In addition no other regions of the brain showed signs of glial activation. In the sham group, glial activation was found in the facial nucleus at day 7 and 15. The time course and anatomic localization of glial activations were confirmed by in vivo [ 18 F]-GE180 autoradiography and Nissl-staining. Conclusions Glial activation takes place in the ipsilesional vestibular and cochlear nucleus within the first 30 days after an inner ear lesion and thereby parallels the establishment of central vestibular compensation. μ PET is a feasible method to show upregulation of the tspo protein in vivo as a sign of reactive gliosis induced by unilateral labyrinthectomy. Our data suggest that synthetic tspo ligands may be a novel therapeutic principle to augment central vestibular compensation.

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.

Free to read The progression of β-amyloid deposition in the brains of mice overexpressing Swedish mutant β-amyloid precursor protein (APP-Swe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel β-amyloid tracer 18F-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 18F-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 β-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. 18F-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 18F-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 β-amyloid tracer 18F-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.

The transition from mild sedation to deep anaesthesia is marked by the phenomenon of burst suppression (BS). FDG-PET studies show that the cerebral metabolic rate for glucose (CMRglc) declines dramatically with onset of BS in the adult brain. Global CMRglc increases substantially in the post-natal period and achieves its maximum in preadolescence. However, the impact of post-natal brain development on the vulnerability of CMRglc to the onset of BS has not been documented. Therefore, cerebral blood flow and metabolism were measured using a variant of the Kety-Schmidt method, in conjunction with quantitative regional estimation of brain glucose uptake by FDG-PET in groups of neonate and juvenile pigs, under a condition of light sedation or after induction of deep anaesthesia with thiopental. Quantification of simultaneous ECoG recordings was used to establish the correlation between anaesthesia-related changes in brain electrical activity and the observed cerebrometabolic changes. In the condition of light sedation the magnitude of CMRglc was approximately 20% higher in the older pigs, with the greatest developmental increase evident in the cerebral cortex and basal ganglia (P

Positron emission tomography (PET) shows reduced binding of the dopamine D(2/3) antagonist [(11) C]raclopride in striatum of withdrawn psychostimulant abusers, but not consistently in patients with alcohol dependence (AD). We make first use of the high affinity ligand [(18) F]fallypride to obtain serial measures of D(2/3) receptor availability in striatal and extrastriatal regions of AD patients undergoing detoxification. Seventeen patients (mean age 44 ± 5y) with AD and 14 age-matched healthy volunteers participated. Each patient underwent [(18) F]fallypride PET upon hospital admission, and again 1-2 weeks later; two patients achieving abstinence, and two with substantial harm reduction had additional PET follow-up at 1 year. Dynamic 180-minute PET recordings were used for volume of interest (VOI)-based and voxel-wise analysis of [(18) F]fallypride binding potential (BP(ND) ). Mean baseline BP(ND) in striatum of the AD patients (15.7 ± 3.6) was unaltered during short-term follow-up, and did not differ from that in healthy controls (16.8 ± 3.0); however, BP(ND) was 10-20% lower in thalamus, hippocampus, and insular and temporal cortex of the AD patients (P 0.05). Age-dependent declines in BP(ND) were very small in controls, but more pronounced and widespread in the AD group. Striatal and thalamic BP(ND) increased by 30% in four patients with long-term abstinence or reduced alcohol consumption. VOI-based [(18) F]fallypride PET analyses revealed group differences in D(2/3) receptor availability primarily in extra-striatal regions. Age-related loss of dopamine D(2/3) receptors was more pronounced in AD patients. Receptor availability was unaltered by acute withdrawal, but increased in the subgroup of patients with long-term follow-up, suggesting reversibility of receptor changes.

To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [(18)F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs).Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [(18)F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg·kg(-1) bolus + 1 mg·kg(-1)·h(-1) continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input.Plasma [(18)F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUV(max) was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUV(max) 1.53 ± 0.32). Administration of NS6740 significantly decreased [(18)F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BP(ND). The baseline BP(ND) ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BP(ND) in regions with high [(18)F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BP(ND) in low binding regions (cerebellum: -16%, p = 0.2).This study confirms the potential of [(18)F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET.

Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders.We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [(18) F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders.Mean baseline parametric maps of the [(18) F]MPPF unidirectional blood-brain clearance (K(1) ; ml/g per min) and the efflux rate constant (k(2) ; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [(18) F]MPPF K(1) in hippocampus by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [(18) F]MPPF k(2) in hippocampus by 27% in nonresponders, without comparable effects in the responder group.These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [(18) F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P-glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to individual differences in P-glycoprotein expression.

The relationship between the photon beam quality specifier %dd(10)x and the Spencer-Attix water water to air restricted mass collision stopping-power ratio, (L/rho))air(water), is studied using Monte Carlo simulation with realistic beams in contrast to the previously used realistic but uniform spectra from an isotropic point source. The differences between accelerators with and without flattening filters are investigated since flattening filter free accelerators appear to be useful for IMRT. Our results show that the standard relationship between %dd(10)x and (L/rho)air(water), which is used in the TG-51 protocol to calculate the quality conversion factor kQ, is acceptable for beams with or without a flattening filter with a maximum error of 0.4%, although a fit to the new data would reduce the maximum error to 0.2%. Reasons for differences between the individual values of %dd(10)x and (L/ rho)air(water) with and without a flattening filter are studied. Specifically the differences due to the softening of the beam, the change in shape of the profile, and the inclusion of radial variations in the photon energy spectra, are investigated. It is shown that if TPR10(20) is used as a beam quality specifier, there are two different relationships between TPR10(20) and (L/rho)air(water) which differ by 0.4%-1%. When using TPR10(20) as a beam quality specifier in a beam without a flattening filter, one should subtract 0.5% from the value of kQ for a given value of TPR10(20).

Introduction A recent case series study showed significant improvements of symptoms in patients with cerebellar ataxia on medication with the amino acid acetyl-dl-leucine (Tanganil) (Strupp et al., 2013). In analogy to electrophysiological studies in animals it was hypothesized that acetyl-DL-leucine modulates the activity of central vestibular neurons, preferably in the cerebellum, by normalizing the membrane potential of depolarized or hyperpolarized neurons and thereby improves central compensation. However, the mode of action of acetyl-dl-leucine and the site of central compensation remained speculative. To deepen our insights in the central compensatory processes induced by acetyl-dl-leucine we performed a FDG-PET study in cerebellar ataxic patients off and on treatment. Methods 21 patients with cerebellar ataxia of different etiologies were scanned by resting state FDG-PET twice, (A) off treatment (PET 1), and a second time (B) ⩾3months on treatment with 5g/day acetyl-dl-leucine (PET 2; n =18). At both time points the patients underwent a detailed neurological examination and measurements of standardized ataxia scales (SARA, SCAFI). Group subtraction analyses (PET 1 vs. PET 2; responders vs. non-responders) as well as statistical group comparisons with age- and gender-matched healthy controls were calculated with statistical parametric mapping (SPM). Results The contrast on vs. off treatment (PET 2 vs. PET 1) mainly showed signal differences in the mesencephalon (midbrain integration centers) as well as in the lateral medullary brainstem (vestibular nucleus region), thalami and midinsular regions bilaterally. The contrast PET 1 vs. PET 2 revealed signal differences in the posterior insula as well as in primary and secondary visual areas (including MT/V5) bilaterally. Restricting the analyses to treatment-responders ( n =11), PET 2 vs. PET 1 showed similar signal areas in the central midbrain and dorsal medullary brainstem bilaterally that were lacking in the corresponding contrast of the non-responders ( n =6). In the direct comparison of responders vs. non-responders PET 2 signal differences were located in both caudate nuclei, the superior temporal gyrus and hippocampus. The signal in responders – mainly in the posterior insula and the medial temporal gyrus – was lower compared to non-responders. In all contrasts cerebellar signal changes were sparse. Conclusions Central compensatory processes induced by acetyl-dl-leucine in cerebellar ataxia seem to involve mainly centers in the medulla (vestibular nuclei), midbrain (vestibular integration centers), thalami, basal ganglia and insular regions rather than neurons in the cerebellum, the primary site of dysfunction in cerebellar ataxia syndromes.

Background and aim Primary orthostatic tremor (OT) is a rare neurological disease of unknown pathophysiology characterized by a high frequency tremor mainly of the legs when standing. The aim of the present study was to depict the cerebral tremor network in OT by [ 18 F]-FDG-PET during standing. Methods Ten patients (mean age 58 ± 12 years) with neurophysiologically proven OT (EMG, posturography) and ten age-matched healthy controls were included in the study. All subjects underwent a [ 18 F]-FDG-PET paradigm during real standing (i.e. injection of [ 18 F]-FDG during upright stance, PET scan 30 min p.i.). As a control condition in a second session a PET was acquired after injection of [ 18 F]-FDG in lying position. PET images were processed by SPM8 software and compared between groups and conditions. Results All patients but no control subject showed a characteristic high-frequency peak at 12–16 Hz in posturography. In healthy subjects the regional cerebral glucose metabolism (rCGM) during standing compared to lying was increased in the vermal cerebellum, thalamus and primary motor region. During standing, OT patients had a relatively increased rCGM in the cerebellum (including the dentate nucleus), the ventrointermediate nucleus of the thalamus and the primary and supplementary motor cortex bilaterally in comparison to the control group. A relatively decreased rCGM was found in the mesiofrontal cortical areas in OT patients during standing. Conclusions In the present study a cerebello–thalamo–cortical tremor network is depicted in a group of OT patients using [ 18 F]-FDG-PET during standing. The data strongly reinforce the idea that the ventrointermediate nucleus of the thalamus may be a therapeutic target for deep brain stimulation in OT.

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.

Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of e = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1999–2012, 2003

The formation mechanism of an alanine-based peptide has been studied by all-atom molecular dynamics simulations with a recently developed all-atom point-charge force field and the Generalize Born continuum solvent model at an effective salt concentration of 0.2M. Thirty-two simulations were conducted. Each simulation was performed for 100 ns. A surprisingly complex folding process was observed. The development of the helical content can be divided into three phases with time constants of 0.06-0.08, 1.4-2.3, and 12-13 ns, respectively. Helices initiate extreme rapidly in the first phase similar to that estimated from explicit solvent simulations. Hydrophobic collapse also takes place in this phase. A folding intermediate state develops in the second phase and is unfolded to allow the peptide to reach the transition state in the third phase. The folding intermediate states are characterized by the two-turn short helices and the transition states are helix-turn-helix motifs-both of which are stabilized by hydrophobic clusters. The equilibrium helical content, calculated by both the main-chain Phi-Psi torsion angles and the main-chain hydrogen bonds, is 64-66%, which is in remarkable agreement with experiments. After corrected for the solvent viscosity effect, an extrapolated folding time of 16-20 ns is obtained that is in qualitative agreement with experiments. Contrary to the prevailing opinion, neither initiation nor growth of the helix is the rate-limiting step. Instead, the rate-limiting step for this peptide is breaking the non-native hydrophobic clusters in order to reach the transition state. The implication to the folding mechanisms of proteins is also discussed.

13 pages, 7 figures, 1 table, 1 appendix.-- PACS numbers: 47.54.+r, 47.20.Lz, 47.20.Bp, 47.27.Te, We present the results of a wavelet-based approach to the study of the chaotic dynamics of a one dimensional model that shows a direct transition to spatiotemporal chaos. We find that the dynamics of this model in the spatiotemporally chaotic regime may be understood in terms of localized dynamics in both space and scale (wavenumber). A projection onto a Daubechies basis yields a good separation of scales, as shown by an examination of the contribution of different wavelet levels to the power spectrum. At most scales, including the most energetic ones, we find essentially Gaussian dynamics. We also show that removal of certain wavelet modes can be made without altering the dynamics of the system as described by the Lyapunov spectrum., This work was supported by NSF grant DRM9813409 and the Ministerio de Ciencia y Tecnología (Spain) and FEDER, projects BFM2001-0341-C02-01 and BMF2000-1108. One of us (GX) would like to acknowledge the support of a grant from the China Scholarship Council.

Objective: To measure the occupancy of dopamine D2/3 receptors using the D2/3 receptor antagonist [18F]-fallypride (FP) and PET in patients with Parkinson9s disease (PD) on and off medication with the D3-preferring agonist pramipexol. Background The therapeutic occupancy of brain dopamine receptors by various neuroleptics has been repeatedly investigated using [11C]-raclopride PET and [123I]-IBZM SPECT competition paradigms in schizophrenic patients. These studies generally showed that therapeutic response is obtained with blockade of 60-80% of striatal dopamine D2/3 receptors with lower D2/3 occupancy during treatment with the atypical antipsychotic clozapine. However, therapeutic D2/3 occupancy for dopamine D2/3 receptor agonists in patients with PD is scarcely documented. Design/Methods: Four patients with PD (early disease stage, mean age: 59 years) participated after informed consent was obtained. First they underwent a baseline FP PET scan (three-hour dynamic emission recording) during pramipexol monotherapy (3x0.7 mg/d). Two weeks later, they had an otherwise identical FP PET scan after pause of medication for 48-72 hours. Parametric maps of the FP binding potential (BPND) were calculated relative to a cerebellum reference region. Results: The mean FP BPND (± SD) was 15.6±2.4 in the entire putamen and 1.1±0.3 in the thalamus in patients during stable pramipexol monotherapy. Binding results in a group of healthy subjects (n=49) were not significantly different. During pause of medication, FP BPND showed an increase of 9% in the right thalamus (p=0.2) and was unaltered in the putamen, despite a manifest improvement in motor symptoms (UPDRS). Conclusions: We present the first results on therapeutic D2/3 occupancy for a dopamine D2/3 receptor agonist in PD. Assuming that therapeutically effective pramipexol occupancy at brain D2/3 receptors is approximately 10% in PD, which is close to the test-retest stability of the FP PET endpoint, present methods should be fit for detecting further regional occupancy differences in a group of 12-15 patients. Disclosure: Dr. Deutschlander has nothing to disclose. Dr. La Fougere has nothing to disclose. Dr. Xiong has nothing to disclose. Dr. Botzel has nothing to disclose. Dr. Grunder has nothing to disclose. Dr. Cumming has nothing to disclose.