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Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as [11C]-ABP688, a radioligand. This open-label, single-center pilot study estimates extent of occupancy of mGluR5 receptors following single oral doses of mavoglurant, using [11C]-ABP688 positron emission tomography (PET) imaging, in six healthy males aged 20–40 years. This study comprised three periods and six subjects were divided into two cohorts. On Day 1 (Period 1), baseline clinical data and safety samples were obtained along with PET scan. During Period 2 (1–7 days after Period 1), cohort 1 and 2 received mavoglurant 25 mg and 100 mg, respectively. During Period 3 (7 days after Period 2), cohort 1 and 2 received mavoglurant 200 mg and 400 mg, respectively. Mavoglurant showed the highest distribution volumes in the cingulate region with lower uptake in cerebellum and white matter, possibly because myelinated axonal sheets maybe devoid of mGlu5 receptors. Maximum concentrations of mavoglurant were observed around 2–3.25 h post-dose. Mavoglurant passed the blood–brain barrier and induced dose- and exposure-dependent displacement of [11C]-ABP688 from the mGluR5 receptors, 3–4 h post-administration (27%, 59%, 74%, 85% receptor occupancy for mavoglurant 25 mg, 100 mg, 200 mg, 400 mg dose, respectively). There were no severe adverse effects or clinically significant changes in safety parameters. This is the first human receptor occupancy study completed with Mavoglurant. It served to guide the dosing of mavoglurant in the past and currently ongoing clinical studies. Furthermore, it confirms the utility of [11C]-ABP688 as a unique tool to study drug-induced occupancy of mGlu5 receptors in the living human brain., NeuroImage, 230, ISSN:1053-8119, ISSN:1095-9572

Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as [

The SAFIR collaboration is currently developing a high-rate positron emission tomography (PET) insert to study fast kinetic processes in small animals. Our insert is designed for simultaneous image acquisition with a preclinical 7 T magnetic resonance (MR) imaging device. In contrast to existing preclinical PET scanners and inserts, our hardware is optimized for high-rate measurements with source activities up to 500 MBq. As a first step, the SAFIR Prototype insert was constructed. This already incorporates the final components, but has a reduced axial field-of-view (35.6 mm). We use lutetiumyttrium oxyorthosilicate crystals (2.12 mm × 2.12 mm × 13 mm) one-to-one coupled to silicon photomultipliers. All analog signals are digitized within the insert. We use 49 MR-compatible dc- dc converters in the insert to provide the power to all readout electronics. After shimming, no degradation of the homogeneity of the static B0 field in the MR scanner was observed. During full operation, we saw a minor reduction in the signal-to-noise ratio of the MR data of 4.9%. With a low activity point source (22Na 0.65 MBq) we obtained a coincidence energy resolution of 13.8% full width at half maximum (FWhM) and a coincidence timing resolution of 194 ps (FWhM). First PET/MR rat brain and high-rate mouse cardiac images (84.9 MBq) are shown in this article., IEEE Transactions on Radiation and Plasma Medical Sciences, 4 (5), ISSN:2469-7311

Background: The amyloid cascade hypothesis characterizes the stereotyped progression of pathological changes in Alzheimer’s disease (AD) beginning with beta amyloid deposition, but does not address the reasons for amyloid deposition. Brain areas with relatively higher neuronal activity, metabolic demand, and production of reactive oxygen species in earlier life may have higher beta amyloid deposition in later life. The aim of this study was to investigate early life patterns of perfusion and late life patterns of amyloid deposition to determine the extent to which normative cerebral perfusion predisposes specific regions to future beta amyloid deposition. Materials and Methods: One hundred twenty-eight healthy, older human subjects (age: 56–87 years old; 44% women) underwent positron emission tomography (PET) imaging with [ 11 C]PiB for measures of amyloid burden. Cerebral perfusion maps derived from 47 healthy younger adults (age: 22–49; 47%) who had undergone single photon emission computed tomography (SPECT) imaging, were averaged to create a normative template, repre- sentative of young, healthy adults. Perfusion and amyloid measures were investigated in 31 cortical regions from the Hammers atlas. We examined the spatial relationship between normative perfusion patterns and amyloid pathophysiology. Results: The pattern of increasing perfusion (temporal lobe < parietal lobe < frontal lobe < insula/cingulate gyrus < occipital lobe; F(4,26) = 7.8, p = 0.0003) in young, healthy adults was not exactly identical to but approximated the pattern of increasing amyloid burden (temporal lobe < occipital lobe < frontal lobe < parietal lobe < insula/cingulate gyrus; F(4,26) = 5.0, p = 0.004) in older adults. However, investigating subregions within cortical lobes provided consistent agreement between ranked normative perfusion patterns and expected Thal staging of amyloid progression in AD (Spearman r = 0.39, p = 0.03). Conclusion: Our findings suggest that brain areas with normatively greater perfusion may be more susceptible to amyloid deposition in later life, possibly due to higher metabolic demand, and associated levels of oxidative stress and inflammation.

Background The purpose of this study was to assess the impact of vendor-provided atlas-based MRAC on FDG PET/MR for the evaluation of Alzheimer’s disease (AD) by using simulated images. Methods We recruited 47 patients, from two institutions, who underwent PET/CT and PET/MR (GE SIGNA) examination for oncological staging. From the PET raw data acquired on PET/MR, two FDG-PET series were generated, using vendor-provided MRAC (atlas-based) and CTAC. The following simulation steps were performed in MNI space: After spatial normalization and smoothing of the PET datasets, we calculated the error map for each patient, PETMRAC/PETCTAC. We multiplied each of these 47 error maps with each of the 203 Alzheimer’s Disease Neuroimaging Initiative (ADNI) cases after the identical normalization and smoothing. This resulted in 203*47 = 9541 datasets. To evaluate the probability of AD in each resulting image, a cumulative t-value was calculated automatically using commercially-available software (PMOD PALZ) which has been used in multiple large cohort studies. The diagnostic accuracy for the discrimination of AD and predicting progression from mild cognitive impairment (MCI) to AD were evaluated in simulated images compared with ADNI original images. Results The accuracy and specificity for the discrimination of AD-patients from normal controls were not substantially impaired, but sensitivity was slightly impaired in 5 out of 47 datasets (original vs. error; 83.2% [CI 75.0%-89.0%], 83.3% [CI 74.2%-89.8%] and 83.1% [CI 75.6%-88.3%] vs. 82.7% [range 80.4–85.0%], 78.5% [range 72.9–83.3%,] and 86.1% [range 81.4–89.8%]). The accuracy, sensitivity and specificity for predicting progression from MCI to AD during 2-year follow-up was not impaired (original vs. error; 62.5% [CI 53.3%-69.3%], 78.8% [CI 65.4%-88.6%] and 54.0% [CI 47.0%-69.1%] vs. 64.8% [range 61.5–66.7%], 75.7% [range 66.7–81.8%,] and 59.0% [range 50.8–63.5%]). The worst 3 error maps show a tendency towards underestimation of PET scores. Conclusion FDG-PET/MR based on atlas-based MR attenuation correction showed similar diagnostic accuracy to the CT-based method for the diagnosis of AD and the prediction of progression of MCI to AD using commercially-available software, although with a minor reduction in sensitivity.

Introduction Metabotropic glutamate receptors play a critical role in the pathogenesis of Alzheimer's disease due to their involvement in processes of memory formation, neuroplasticity, and synaptotoxity. The objective of the current study was to study mGluR5 availability measured by [11C]‐ABP688 (ABP) in patients with clinically diagnosed Alzheimer's dementia (AD). Methods A bolus‐infusion protocol of [11C]‐ABP688 was applied in 9 subjects with AD and 10 cognitively healthy controls (Controls) to derive distribution volume estimates of mGluR5. Furthermore, we also estimated cerebral perfusion by averaging early frame signal of initial ABP bolus injection. Results Subjects with Alzheimer's dementia (mean age: 77.3/SD 5.7) were older than controls (mean age: 68.5/SD : 9.6) and scored lower on the MMSE (22.1/SD2.7 vs. 29.0/SD0.8). There were no overall differences in ABP signal. However, distribution volume ratio (DVR) for ABP was reduced in the bilateral hippocampus (AD: 1.34/SD : 0.40 vs. Control: 1.84/SD :0.31, p = .007) and the bilateral amygdala (AD:1.86/SD :0.26 vs. Control:2.33/SD :0.37 p = .006) in AD patients compared to controls. Estimate of cerebral blood flow was reduced in the bilateral hippocampus in AD (AD:0.75/SD :0.10 vs. Control:0.86/SD :0.09 p = .02). Conclusion Our findings demonstrate reduced mGluR5 binding in the hippocampus and amygdala in Alzheimer's dementia. Whether this is due to synaptic loss and/or consecutive reduction of potential binding sites or reflects disease inherent mechanisms remains to be elucidated in future studies., Brain and Behavior, 10 (6), ISSN:2162-3279

PURPOSE To investigate the diagnostic value of F-fluoroethyl-L-tyrosine (FET) positron emission tomography (PET) in patients with suspected tumefactive demyelinating disease. METHODS We retrospectively examined FET-PET and MR imaging of 21 patients (12 female, 9 male) with known demyelinating disease and newly diagnosed tumefactive lesions. The maximum standardized uptake value (SUVmax), time activity curves (TAC) and lesion-to-background ratio (TBR) of these lesions were calculated. The standard of reference consisted of biopsy and/or follow-up imaging. FET parameters of true neoplastic lesions and tumefactive demyelinating lesions were compared using Mann-Whitney U-test and receiver operating characteristic (ROC) analysis. RESULTS Nine patients (42.9%) had neoplastic lesions, 12 patients (57.1%) had tumefactive demyelinating lesions. TBRmax, SUVmax and TAC were significantly different between demyelinating lesions and neoplastic lesions: Tumors had a higher TBRmax (3.53 ± 1.09 vs. 1.48 ± 0.31, respectively; P < 0.001) and SUVmax (3.95 ± 1.59 vs. 1.86 ± 0.50, respectively; P < 0.001) than tumefactive demyelinating lesions. The TAC of tumors was significantly higher compared to tumefactive demyelinating lesions at all time points (P < 0.05). ROC analysis revealed that a TBRmax threshold of 2.2 and a SUVmax threshold of 2.5 could reliably differentiate tumor and tumefactive demyelination (area under the curve, 1.000 and 0.958, respectively). CONCLUSION In patients with demyelinating disease, FET-PET parameters TBRmax (cut-off 2.2) and SUVmax (cut-off 2.5) are able to distinguish tumefactive demyelinations from true neoplastic lesions.

ObjectiveTo study blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) as a surrogate imaging marker for crossed cerebellar diaschisis (CCD).MethodsTwenty-five participants with symptomatic unilateral cerebrovascular steno-occlusive disease underwent a BOLD-CVR and an acetazolamide challenged (15O)-H2O-PET study. CCD and cerebellar asymmetry index were determined from PET and compared to BOLD-CVR quantitative values. Neurologic status at admission and outcome after 3 months were determined with NIH Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores.ResultsFor both the BOLD-CVR and PET examination, a significant cerebellar asymmetry index was found for participants exhibiting CCD (CCD+ vs CCD−: for BOLD-CVR 13.11 ± 9.46 vs 1.52 ± 4.97, p < 0.001; and for PET 7.31 ± 2.75 vs 1.68 ± 2.98, p < 0.001). The area under the curve for BOLD-CVR was 0.89 (95% confidence interval: 0.75–1.0) with 0.91 sensitivity and 0.81 specificity to detect CCD. Participants exhibiting CCD were in poorer clinical condition at baseline (CCD+ vs CCD−: NIHSS 7 vs 1, p = 0.003; mRS 3 vs 1, p = 0.001) and after 3-month follow-up (NIHSS 2 vs 0, p = 0.02; mRS 1 vs 0, p = 0.04). Worse performance on both scores showed an agreement with a larger BOLD-CVR cerebellar asymmetry index. This was not found for PET.ConclusionsBOLD-CVR demonstrates similar sensitivity to detect CCD as compared to (15O)-H2O-PET in patients with symptomatic unilateral cerebrovascular steno-occlusive disease. Furthermore, participants exhibiting CCD had a poorer baseline neurologic performance and neurologic outcome at 3 months.Classification of evidenceThis study provides Class II evidence that BOLD-CVR identifies CCD in patients with symptomatic unilateral cerebrovascular steno-occlusive disease.

Background Moyamoya disease is a steno-occlusive disease of the circle of Willis with growth of pathologic collaterals. We compared functional perfusion imaging ([15O]water-positron emission tomography [PET] with acetazolamide challenge) with conventional magnetic resonance imaging (MRI) and angiography for determining indication for cerebral revascularization in patients with moyamoya. Methods We performed a retrospective blinded analysis of individual imaging modalities (MRI, angiography, PET) and scored each modality for severity of disease in 21 untreated patients with moyamoya with 78 affected vascular territories. Results Positive predictive value to identify insufficient perfusion on angiography and MRI together was 98.3% as proven on combined PET/computed tomography. Negative predictive value to identify sufficient perfusion on angiography and/or MRI only was 60%. Negative predictive value to predict good perfusion on PET based on MRI (no infarctions in the respective territory) was only 17%. An assumed good perfusion based on the suggestion of good collaterals on angiography was correct in only 13.4% of cases. Positive predictive value (angiography of main vessel and weak or no collateralization) to predict insufficient perfusion on PET/computed tomography was 76.9%; negative predictive value (angiography of main vessel and strong collateralization) to identify good perfusion was 13.4%. Conclusions Reliable evaluation of cerebral blood flow might not be possible with angiography and basic MRI alone. We strongly recommend additional functional imaging (e.g., [15O]water-PET with acetazolamide challenge) to precisely evaluate the indication for cerebral revascularization.

The accumulation of β-amyloid plaques is a hallmark of Alzheimer's disease (AD), and recently published data suggest that increased brain iron burden may reflect pathologies that synergistically contribute to the development of cognitive dysfunction. While preclinical disease stages are considered most promising for therapeutic intervention, the link between emerging AD-pathology and earliest clinical symptoms remains largely unclear. In the current study we therefore investigated local correlations between iron and β-amyloid plaques, and their possible association with cognitive performance in healthy older adults. 116 older adults (mean age 75 ± 7.4 years) received neuropsychological testing to calculate a composite cognitive score of performance in episodic memory, executive functioning, attention, language and communication. All participants were scanned on a combined PET-MRI instrument and were administered T1-sequences for anatomical mapping, quantitative susceptibility mapping (QSM) for assessing iron, and 18F-Flutemetamol-PET for estimating β-amyloid plaque load. Biological parametric mapping (BPM) was used to generate masks indicating voxels with significant (p 0.05) correlation between susceptibility and 18F-Flutemetamol-SUVR. We found a bilateral pattern of clusters characterized by a statistical relationship between magnetic susceptibility and 18F-Flutemetamol-SUVR, indicating local correlations between iron and β-amyloid plaque deposition. For two bilateral clusters, located in the frontal and temporal cortex, significant relationships (p0.05) between local β-amyloid and the composite cognitive performance score could be observed. No relationship between whole-cortex β-amyloid plaque load and cognitive performance was observable. Our data suggest that the local correlation of β-amyloid plaque load and iron deposition may provide relevant information regarding cognitive performance of healthy older adults. Further studies are needed to clarify pathological correlates of the local interaction of β-amyloid, iron and other causes of altered magnetic susceptibility.

The small animal fast insert for mRi (SAFIR) positron emission tomography insert was proposed for quantitative dynamic acquisition inside a preclinical 7T magnetic resonance imaging scanner to study kinetics of short-lived tracers. For this purpose, the SAFIR readout should be capable of handling high count rates and achieving excellent timing performance. We evaluated one of the available application specific integrated circuits (ASICs) for SiPM readout, namely SiPM timing chip (STiC) version 3.1. In this paper, we show the performances of the SAFIR PET detector with the STiC ASIC readout. The SAFIR PET detector consists of an $8 \times 8$ array of lutetium yttrium oxyorthosilicate $2.1\,\,{\mathrm {mm}} \times 2.1\,\,{\mathrm {mm}} \times 12$ mm crystals coupled, with optical grease, to an $8 \times 8$ array of SiPMs with a $2.0\,\,{\mathrm {mm}} \times 2.0$ mm photo-sensitive area. Signals from the individual SiPM channels were digitized by the STiC ASIC. Hit’s arrival time and time-over-threshold (TOT) were recorded into time stamps with 50.2-ps least significant bit. We obtained an average energy resolution of 18.5% full width at half maximum (FWHM) at 511-keV photopeak after TOT nonlinearity correction and an average coincidence resolving time resolution of 244-ps FWHM with time walk correction that satisfy our requirements specification on the detector performance.

Background and Purpose— Increased stroke risk correlates with hemodynamic failure, which can be assessed with ( 15 O-)H 2 O positron emission tomography (PET) cerebral blood flow (CBF) measurements. This gold standard technique, however, is not established for routine clinical imaging. Standardized blood oxygen-level–dependent (BOLD) functional magnetic resonance imaging+CO 2 is a noninvasive and potentially widely applicable tool to assess whole-brain quantitative cerebrovascular reactivity (CVR). We examined the agreement between the 2 imaging modalities and hypothesized that quantitative CVR can be a surrogate imaging marker to assess hemodynamic failure. Methods— Nineteen data sets of subjects with chronic cerebrovascular steno-occlusive disease (age, 60±11 years; 4 women) and unilaterally impaired perfusion reserve on Diamox-challenged ( 15 O-)H 2 O PET were studied and compared with a standardized BOLD functional magnetic resonance imaging+CO 2 examination within 6 weeks (8±19 days). Agreement between quantitative CBF- and CVR-based perfusion reserve was assessed. Hemodynamic failure was staged according to PET findings: stage 0: normal CBF, normal perfusion reserve; stage I: normal CBF, decreased perfusion reserve; and stage II: decreased CBF, decreased perfusion reserve. The BOLD CVR data set of the same subjects was then matched to the corresponding stage of hemodynamic failure. Results— PET-based stage I versus stage II could also be clearly separated with BOLD CVR measurements (CVR for stage I 0.11 versus CVR for stage II −0.03; P P R 2 =0.47 and P =0.02, R 2 = 0.25, respectively). Conclusions— BOLD CVR corresponded well to CBF perfusion reserve measurements obtained with ( 15 O-)H 2 O-PET, especially for detecting hemodynamic failure in the affected hemisphere and middle cerebral artery territory and for identifying hemodynamic failure stage II. BOLD CVR may, therefore, be considered for prospective studies assessing stroke risk in patients with chronic cerebrovascular steno-occlusive disease, in particular because it can potentially be implemented in routine clinical imaging.

Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability. In the present study, we investigated mGluR5 in vivo in patients with alcohol use disorder without the confounding effects of smoking. A total of 14 male subjects with alcohol use disorder and at least a 25-day abstinence and 14 matched male non-smoking healthy controls were included in the study. We employed positron emission tomography (PET) with the mGluR5-specific radiotracer [11C]ABP688, using a bolus/infusion protocol. We found increased mGluR5 DVR in several regions within the temporal lobe in patients, as compared to controls. The largest between-group difference was in the amygdala. There was a marked positive relation between mGluR5 DVR in the anterior cingulate and mGluR5 DVR in the orbitofrontal cortex in patients, but not in controls. In patients, lower temptation to drink was related to higher amygdala mGluR5 DVR. We did not find altered mGluR5 DVR in the basal ganglia of subjects recovering from alcohol use disorder. In conclusion, our study provides clinical evidence for altered mGluR5 signaling in the amygdala in alcohol use disorder. This alteration was associated with the temptation to drink. In addition, this study suggests abnormal mGluR5 signaling in a network underlying reward-related behavioral flexibility. These findings strengthen the case for pharmacological agents acting on mGluR5 as promising candidates for the treatment of alcohol use disorder., Translational Psychiatry, 8 (1), ISSN:2158-3188

Non-invasive imaging of metabotropic glutamate receptor 5 (mGlu5) in the brain using PET is of interest in e.g., anxiety, depression, and Parkinson’s disease. Widespread application of the most widely used mGlu5 tracer, [11C]ABP688, is limited by the short physical half-life of carbon-11. [18F]PSS232 is a fluorinated analog with promising preclinical properties and high selectivity and specificity for mGlu5. In this first-in-man study, we evaluated the brain uptake pattern and kinetics of [18F]PSS232 in healthy volunteers. [18F]PSS232 PET was performed with ten healthy male volunteers aged 20–40 years. Seven of the subjects received a bolus injection and the remainder a bolus/infusion protocol. Cerebral blood flow was determined in seven subjects using [15O]water PET. Arterial blood activity was measured using an online blood counter. Tracer kinetics were evaluated by compartment modeling and parametric maps were generated for both tracers. At 90 min post-injection, 59.2 ± 11.1% of total radioactivity in plasma corresponded to intact tracer. The regional first pass extraction fraction of [18F]PSS232 ranged from 0.41 ± 0.06 to 0.55 ± 0.03 and brain distribution pattern matched that of [11C]ABP688. Uptake kinetics followed a simple two-tissue compartment model. The volume of distribution of total tracer (V T, ml/cm3) ranged from 1.18 ± 0.20 for white matter to 2.91 ± 0.51 for putamen. The respective mean distribution volume ratios (DVR) with cerebellum as the reference tissue were 0.88 ± 0.06 and 2.12 ± 0.10, respectively. The tissue/cerebellum ratios of a bolus/infusion protocol (30/70 dose ratio) were close to the DVR values. Brain uptake of [18F]PSS232 matched the distribution of mGlu5 and followed a two-tissue compartment model. The well-defined kinetics and the possibility to use reference tissue models, obviating the need for arterial blood sampling, make [18F]PSS232 a promising fluorine-18 labeled radioligand for measuring mGlu5 density in humans.

The SAFIR development represents a novel Positron Emission Tomography (PET) detector, conceived for preclinical fast acquisitions inside the bore of a Magnetic Resonance Imaging (MRI) scanner. The goal is hybrid and simultaneous PET/MRI dynamic studies at unprecedented temporal resolutions of a few seconds. The detector relies on matrices of scintillating LSO-based crystals coupled one-to-one with SiPM arrays and readout by fast ASICs with excellent timing resolution and high rate capabilities. The paper describes the detector concept and the initial results in terms of simulations and characterisation measurements.

Background Effects of beta-amyloid accumulation on neuronal function precede the clinical manifestation of Alzheimer's disease (AD) by years and affect distinct cognitive brain networks. As previous studies suggest a link between beta-amyloid and dysregulation of excitatory and inhibitory neurotransmitters, we aimed to investigate the impact of GABA and glutamate on beta-amyloid related functional connectivity. Methods 29 cognitively unimpaired old-aged adults (age = 70.03 ± 5.77 years) were administered 11C-Pittsburgh Compound B (PiB) positron-emission tomography (PET), and MRI at 7 Tesla (7T) including blood oxygen level dependent (BOLD) functional MRI (fMRI) at rest for measuring static and dynamic functional connectivity. An advanced 7T MR spectroscopic imaging (MRSI) sequence based on the free induction decay acquisition localized by outer volume suppression’ (FIDLOVS) technology was used for gray matter specific measures of GABA and glutamate in the posterior cingulate and precuneus (PCP) region. Results GABA and glutamate MR-spectra indicated significantly higher levels in gray matter than in white matter. A global effect of beta-amyloid on functional connectivity in the frontal, occipital and inferior temporal lobes was observable. Interactive effects of beta-amyloid with gray matter GABA displayed positive PCP connectivity to the frontomedial regions, and the interaction of beta-amyloid with gray matter glutamate indicated positive PCP connectivity to frontal and cerebellar regions. Furthermore, decreased whole-brain but increased fronto-occipital and temporo-parietal dynamic connectivity was found, when GABA interacted with regional beta-amyloid deposits in the amygdala, frontal lobe, hippocampus, insula and striatum. Conclusions GABA, and less so glutamate, may moderate beta-amyloid related functional connectivity. Additional research is needed to better characterize their interaction and potential impact on AD., NeuroImage: Clinical, 22, ISSN:2213-1582

Sleep and brain glutamatergic signaling are homeostatically regulated. Recovery sleep following prolonged wakefulness restores efficient functioning of the brain, possibly by keeping glutamatergic signaling in a homeostatic range. Evidence in humans and mice suggested that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain’s coping mechanisms with sleep deprivation. Here, proton magnetic resonance spectroscopy in 31 healthy men was used to quantify the levels of glutamate (Glu), glutamate-to-glutamine ratio (GLX), and γ-amino-butyric-acid (GABA) in basal ganglia (BG) and dorsolateral prefrontal cortex on 3 consecutive days, after ~8 (baseline), ~32 (sleep deprivation), and ~8 hours (recovery sleep) of wakefulness. Simultaneously, mGluR5 availability was quantified with the novel radioligand for positron emission tomography, [18F]PSS232, and the blood levels of the mGluR5-regulated proteins, fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) were determined. The data revealed that GLX (p = 0.03) in BG (for Glu: p < 0.06) and the serum concentration of FMRP (p < 0.04) were increased after sleep loss. Other brain metabolites (GABA, N-acetyl-aspartate, choline, glutathione) and serum BDNF levels were not altered by sleep deprivation (pall > 0.6). By contrast, the night without sleep enhanced whole-brain, BG, and parietal cortex mGluR5 availability, which was normalized by recovery sleep (pall < 0.05). The findings provide convergent multimodal evidence that glutamatergic signaling is affected by sleep deprivation and recovery sleep. They support a role for mGluR5 and FMRP in sleep–wake regulation and warrant further studies to investigate their causality and relevance for regulating human sleep in health and disease., Sleep, 42 (11), ISSN:1550-9109, ISSN:0161-8105

SAFIR is a high-rate PET insert for a preclinical 7 T MRI scanner, aiming at studying fast biological processes in small animals, using tracer activities up to 500 MBq. The full detector comprises 15360 channels, each composed of a LYSO crystal and a $S$ iPM photo-sensor. A dedicated readout system, operating inside the MRI magnet of 200 mm inner diameter acquires 40 kHz of hits per channel. PETA6 ASICs digitize amplitude and time of the hits. FPGAs read, process and transfer, via optical links, the digital data. We present the readout system in detail, together with first test results.

Dopamine D2/D3 receptor availability at rest and its association with individual pain perception was investigated using the [(11)C] raclopride PET-method in 24 female Fibromyalgia (FMS) participants with (FMS+, N=11) and without (FMS-, N=13) comorbid depression and in 17 healthy women. Thermal pain thresholds (TPT) and pain responses were assessed outside the scanner. We compared the discriminative capacity, i.e. the individual׳s capacity to discriminate between lower and higher pain intensities and the response criterion, i.e. the subject׳s tendency to report pain during noxious stimulation due to psychological factors. [(11)C] raclopride binding potential (BP), defined as the ratio of specifically bound non-displaceable radioligand at equilibrium (BP(ND)) was used as measure of D2/D3 receptor availability. We found significant group effects of BP(ND) in striatal regions (left ventral striatum, left caudate nucleus and left nucleus accumbens) between FMS+ and FMS- compared to healthy subjects. Correlational analysis showed negative associations between TPT and D2/D3 receptor availability in the left caudate nucleus in FMS-, between TPT and D2/D3 receptor availability in the right caudate nucleus in FMS + and positive associations between TPT and D2/D3 receptor availability in the left putamen and right caudate nucleus in healthy controls. The response criterion was positively associated with D2/D3 receptor availability in the right nucleus accumbens in FMS - and negatively with D2/D3 receptor availability in the left caudate nucleus in healthy controls. Finally, no significant associations between D2/D3 receptor availability and discriminative capacity in any of the groups or regions were determined. These findings provide further support for a disruption of dopaminergic neurotransmission in FMS and implicate DA as important neurochemical moderator of differences in pain perception in FMS patients with and without co-morbid depression.

Purpose (E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone O-(3-(2-[18F]-fluoroethoxy)propyl) oxime ([18F]-PSS232) is a new PET tracer for imaging of metabotropic glutamate receptor subtype 5 (mGlu5), and has shown promising results in rodents and humans. The aim of this study was to estimate the radiation dosimetry and biodistribution in humans, to assess dose-limiting organs, and to demonstrate safety and tolerability of [18F]-PSS232 in healthy volunteers. Methods PET/CT scans of six healthy male volunteers (mean age 23.5 ± 1.7; 21–26 years) were obtained after intravenous administration of 243 ± 3 MBq of [18F]-PSS232. Serial whole-body (vertex to mid-thigh) PET scans were assessed at ten time points, up to 90 min after tracer injection. Calculation of tracer kinetics and cumulated organ activities were performed using PMOD 3.7 software. Dosimetry estimates were calculated using the OLINDA/EXM software. Results Injection of [18F]-PSS232 was safe and well tolerated. Organs with highest absorbed doses were the gallbladder wall (0.2295 mGy/MBq), liver (0.0547 mGy/MBq), and the small intestine (0.0643 mGy/MBq). Mean effective dose was 3.72 ± 0.12 mSv/volunteer (range 3.61–3.96 mSv; 0.0153 mSv/MBq). Conclusion [18F]-PSS232, a novel [18F]-labeled mGlu5 tracer, showed favorable dosimetry values. Additionally, the tracer was safe and well tolerated.

Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BPND) was assessed from PET data collected with [18F]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [18F]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation.

The CT data acquired in combined PET/CT studies provide a fast and essentially noiseless source for the correction of photon attenuation in PET emission data. To this end, the CT values relating to attenuation of photons in the range of 40-140 keV must be transformed into linear attenuation coefficients at the PET energy of 511 keV. As attenuation depends on photon energy and the absorbing material, an accurate theoretical relation cannot be devised. The transformation implemented in the Discovery LS PET/CT scanner (GE Medical Systems, Milwaukee, Wis.) uses a bilinear function based on the attenuation of water and cortical bone at the CT and PET energies. The purpose of this study was to compare this transformation with experimental CT values and corresponding PET attenuation coefficients. In 14 patients, quantitative PET attenuation maps were calculated from germanium-68 transmission scans, and resolution-matched CT images were generated. A total of 114 volumes of interest were defined and the average PET attenuation coefficients and CT values measured. From the CT values the predicted PET attenuation coefficients were calculated using the bilinear transformation. When the transformation was based on the narrow-beam attenuation coefficient of water at 511 keV (0.096 cm(-1)), the predicted attenuation coefficients were higher in soft tissue than the measured values. This bias was reduced by replacing 0.096 cm(-1) in the transformation by the linear attenuation coefficient of 0.093 cm(-1) obtained from germanium-68 transmission scans. An analysis of the corrected emission activities shows that the resulting transformation is essentially equivalent to the transmission-based attenuation correction for human tissue. For non-human material, however, it may assign inaccurate attenuation coefficients which will also affect the correction in neighbouring tissue.

A 39-year-old Bangladeshi man was admitted to our hospital with a first generalized epileptic seizure. Brain MRI showed multiple ring-enhancing lesions with perifocal edema (Fig. 1a and g, February 2008). CSF analysis showed 8 cells/ll and normal protein, glucose and lactate levels. Serum and CSF serological tests were negative for a broad range of parasites, fungi and bacteria. The patient was suspected to have neurocysticercosis and was treated with albendazole (400 mg bi-daily for 30 days). However, follow up MRI showed new, adjacent lesions with ringand tunnel-shaped enhancement; and punctate calcifications in the left parieto-occipital area in the CT scan (Fig. 1b, h and m, December 2009), suggesting that the treatment had been ineffective. We therefore performed a brain biopsy (with prior MRI for the localization of the sparganum, see Fig. 1c and i, February 2010), which revealed a degenerated cyst containing membrane-shaped structures with multiple foci of calcification. PCR was positive for Spirometra erinaceieuropaei, leading to the diagnosis of cerebral sparganosis. Surgical removal of the parasite is the treatment of choice as standard anti-helmintic therapy is considered ineffective in sparganosis [1–3]. The repeated MRI indicated that the lesion had been wandering again (Fig. 1d and j). An ethylcholine PET showed a defined region with increased tracer uptake, most likely indicating the current location of the sparganum (Fig. 1n). However, the patient refused the recommended stereotactic surgery. We therefore treated the patient with a high-dose regimen of praziquantel (3 9 25 mg/kg body weight daily) for 7 days combined with cimetidine (3 9 400 mg daily) and a high carbohydrate diet to increase plasma levels of praziquantel [4]. The treatment was well-tolerated. Follow-up MRIs 3 and 11 months later showed drastic improvement and the ethylcholine PET had normalized (Fig. 1e, f, k, l, o and p). Anti-sparganum antibody levels were determined from preserved CSF and serum samples by a specific ELISA [5]. Before therapy (Fig. 1, December 2009), anti-sparganum antibody levels were elevated in the serum (0.29) and in the CSF (0.55 normal value in serum and CSF \ 0.22). After therapy (Fig. 1, June 2011), antibody levels had dropped to 0.09 in serum (a lumbar puncture was not repeated after therapy). Seizures discontinued and anticonvulsive treatment was slowly tapered. Sparganosis is a rare parasitic disease caused by infestation with the larval cestode of Spirometra spp. Most cases have been reported in Southeast and Eastern Asia. Humans are infected by drinking unfiltered, contaminated water or through consumption of raw snakes and frogs. When the parasite invades the central nervous system, epileptic seizures and headache are common symptoms [2]. Characteristic MRI findings of cerebral sparganosis include a R. R. Gonzenbach (&) M. Weller A. Semmler Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland e-mail: roman.gonzenbach@usz.ch

For each oncological tracer it is important to know the uptake in non-tumorous lesions. The purpose of this study was to measure the accumulation of fluorine-18 choline (FCH), a promising agent for the evaluation of certain tumour types, in infectious tissue. Unilateral thigh muscle abscesses were induced in five rats by intramuscular injection of 0.1 ml of a bacterial suspension ( Staphylococcus aureus, 1.2 x 10(9) CFU/ml). In all animals, FCH accumulation was measured with high-resolution positron emission tomography (PET) on day 6. Autoradiography of the abscess and ipsilateral healthy muscle was performed on day 7 (three animals) and day 11 (two animals) and correlated with histology. In addition, (18)F-fluorodeoxyglucose (FDG) PET was performed on day 5. Increased FCH uptake was noted in specific layers of the abscess wall which contained an infiltrate of mainly granulocytes on day 7 and mainly macrophages on day 11. The autoradiographic standardised uptake values in the most active part of the abscess wall were 2.99 on day 7 ( n=3) and 4.05 on day 11 ( n=2). In healthy muscle the corresponding values were 0.99 and 0.64. The abscesses were clearly visualised on the FCH and FDG PET images. In conclusion, this study demonstrated avid FCH accumulation in inflammatory tissue, which limits the specificity of FCH for tumour detection. Future studies are now needed to determine the degree of this limitation in human cancer patients.

The protracted accumulation of amyloid-β (Aβ) is a major pathologic hallmark of Alzheimer's disease and may trigger secondary pathological processes that include neurovascular damage. This study was aimed at investigating long-term effects of Aβ burden on cerebral blood volume of arterioles and pial arteries (CBVa), possibly present before manifestation of dementia. Aβ burden was assessed by 11C Pittsburgh compound-B positron emission tomography in 22 controls and 18 persons with mild cognitive impairment (MCI), [ages: 75(±6) years]. After 2 years, inflow-based vascular space occupancy at ultra-high field strength of 7-Tesla was administered for measuring CBVa, and neuropsychological testing for cognitive decline. Crushing gradients were incorporated during MR-imaging to suppress signals from fast-flowing blood in large arteries, and thereby sensitize inflow-based vascular space occupancy to CBVa in pial arteries and arterioles. CBVa was significantly elevated in MCI compared to cognitively normal controls and regional CBVa related to local Aβ deposition. For both MCI and controls, Aβ burden and follow-up CBVa in several brain regions synergistically predicted cognitive decline over 2 years. Orbitofrontal CBVa was positively associated with apolipoprotein E e4 carrier status. Increased CBVa may reflect long-term effects of region-specific pathology associated with Aβ deposition. Additional studies are needed to clarify the role of the arteriolar system and the potential of CBVa as a biomarker for Aβ-related vascular downstream pathology., Neurobiology of Aging, 76, ISSN:0197-4580, ISSN:1558-1497

Alzheimer's disease (AD) is the most common cause of cognitive dysfunction in older adults. The pathological hallmarks of AD such as beta amyloid (Aβ) aggregation and neurometabolic change, as indicated by altered myo-inositol (mI) and N-acetylaspartate (NAA) levels, typically precede the onset of cognitive dysfunction by years. Furthermore, cerebrovascular disease occurs early in AD, but the interplay between vascular and neurometabolic brain change is largely unknown. Thirty cognitively normal older adults (age = 70 ± 5.6 years, Mini-Mental State Examination = 29.2 ± 1) received 11-C-Pittsburgh Compound B positron emission tomography for estimating Aβ-plaque density, 7 Tesla fluid-attenuated inversion recovery magnetic resonance imaging for quantifying white matter hyperintensity volume as a marker of small vessel cerebrovascular disease and high-resolution magnetic resonance spectroscopic imaging at 7 Tesla, based on free induction decay acquisition localized by outer volume suppression to investigate tissue-specific neurometabolism in the posterior cingulate and precuneus. Aβ (β = 0.45, p = 0.018) and white matter hyperintensities (β = 0.40, p = 0.046) were independently and interactively (β = -0.49, p = 0.026) associated with a higher ratio of mI over NAA (mI/NAA) in the posterior cingulate and precuneus gray matter but not in the white matter. Our data suggest that cerebrovascular disease and Aβ burden are synergistically associated with AD-related gray matter neurometabolism in older adults.

Moyamoya disease is a steno-occlusive disease of the circle of Willis with growth of pathologic collaterals. We compared functional perfusion imaging ([We performed a retrospective blinded analysis of individual imaging modalities (MRI, angiography, PET) and scored each modality for severity of disease in 21 untreated patients with moyamoya with 78 affected vascular territories.Positive predictive value to identify insufficient perfusion on angiography and MRI together was 98.3% as proven on combined PET/computed tomography. Negative predictive value to identify sufficient perfusion on angiography and/or MRI only was 60%. Negative predictive value to predict good perfusion on PET based on MRI (no infarctions in the respective territory) was only 17%. An assumed good perfusion based on the suggestion of good collaterals on angiography was correct in only 13.4% of cases. Positive predictive value (angiography of main vessel and weak or no collateralization) to predict insufficient perfusion on PET/computed tomography was 76.9%; negative predictive value (angiography of main vessel and strong collateralization) to identify good perfusion was 13.4%.Reliable evaluation of cerebral blood flow might not be possible with angiography and basic MRI alone. We strongly recommend additional functional imaging (e.g., [

The aging brain is characterized by an increased presence of neurodegenerative and vascular pathologies. However, there is substantial variation regarding the relationship between an individual's pathological burden and resulting cognitive impairment. To identify correlates of preserved cognitive functioning at highest age, the relationship between β-amyloid plaque load, presence of small vessel cerebrovascular disease (SVCD), iron-burden, and brain atrophy was investigated. Eighty cognitively unimpaired participants (44 oldest-old, aged 85-96 years; 36 younger-old, aged 55-80 years) were scanned by integrated positron emission tomography-magnetic resonance imaging for assessing beta regional amyloid plaque load (18F-flutemetamol), white matter hyperintensities as an indicator of SVCD (fluid-attenuated inversion recovery-magnetic resonance imaging), and iron load (quantitative susceptibility mapping). For the oldest-old group, lower cortical volume, increased β-amyloid plaque load, prevalence of SVCD, and lower cognitive performance in the normal range were found. However, compared to normal-old, cortical iron burden was lower in the oldest-old. Moreover, only in the oldest-old, entorhinal cortex volume positively correlated with β-amyloid plaque load. Our data thus indicate that the co-occurrence of aging-associated neuropathologies with reduced quantitative susceptibility mapping measures of cortical iron load constitutes a lower vulnerability to cognitive loss.

Changes in cerebral blood flow are an essential feature of Alzheimer’s disease and have been linked to apolipoprotein E-genotype and cerebral amyloid-deposition. These factors could be interdependent or influence cerebral blood flow via different mechanisms. We examined apolipoprotein E-genotype, amyloid beta-deposition, and cerebral blood flow in amnestic mild cognitive impairment using pseudo-continuous arterial spin labeling MRI in 27 cognitively normal elderly and 16 amnestic mild cognitive impairment participants. Subjects underwent Pittsburgh Compound B (PiB) positron emission tomography and apolipoprotein E-genotyping. Global cerebral blood flow was lower in apolipoprotein E ɛ4-allele carriers (apolipoprotein E4+) than in apolipoprotein E4− across all subjects (including cognitively normal participants) and within the group of cognitively normal elderly. Global cerebral blood flow was lower in subjects with mild cognitive impairment compared with cognitively normal. Subjects with elevated cerebral amyloid-deposition (PiB+) showed a trend for lower global cerebral blood flow. Apolipoprotein E-status exerted the strongest effect on global cerebral blood flow. Regional analysis indicated that local cerebral blood flow reductions were more widespread for the contrasts apolipoprotein E4+ versus apolipoprotein E4− compared with the contrasts PiB+ versus PiB− or mild cognitive impairment versus cognitively normal. These findings suggest that apolipoprotein E-genotype exerts its impact on cerebral blood flow at least partly independently from amyloid beta-deposition, suggesting that apolipoprotein E also contributes to cerebral blood flow changes outside the context of Alzheimer’s disease.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

Intervertebral disc degeneration and disc herniation is one of the major causes of lower back pain. Depletion of extracellular matrix, culminating in nucleus pulposus (NP) extrusion leads to intervertebral disc destruction. Currently available surgical treatments reduce the pain but do not restore the mechanical functionality of the spine. In order to preserve mechanical features of the spine, total disc or nucleus replacement thus became a wide interest. However, this arthroplasty era is still in an immature state, since none of the existing products have been clinically evaluated. This study intends to test the biocompatibility of a novel nucleus implant made of knitted titanium wires. Despite all mechanical advantages, the material has its limits for conventional optical analysis as the resulting implant is non-transparent. Here we present a strategy that describes in vitro visualization, tracking and viability testing of osteochondro-progenitor cells on the scaffold. This protocol can be used to visualize the efficiency of the cleaning protocol as well as to investigate the biocompatibility of these and other non-transparent scaffolds. Furthermore, this protocol can be used to show adherence pattern of cells as well as cell viability and proliferation rates on/in the scaffold. This in vitro biocompatibility testing assay provides a propitious tool to analyze cell-material interaction in non-transparent and opaque scaffolds.

To investigateFET-PET imaging and progression-free survival (PFS) of 16 adult patients with BSG was analyzed (9 high-grade gliomas, 7 low-grade gliomas). SUVProgressive gliomas had higher SUVFET-PET uptake might be associated with disease progression in adult BSG.

Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knock-out mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep.

Increased stroke risk correlates with hemodynamic failure, which can be assessed with (Nineteen data sets of subjects with chronic cerebrovascular steno-occlusive disease (age, 60±11 years; 4 women) and unilaterally impaired perfusion reserve on Diamox-challenged (PET-based stage I versus stage II could also be clearly separated with BOLD CVR measurements (CVR for stage I 0.11 versus CVR for stage II -0.03;BOLD CVR corresponded well to CBF perfusion reserve measurements obtained with (

Non-invasive imaging of metabotropic glutamate receptor 5 (mGlu[At 90 min post-injection, 59.2 ± 11.1% of total radioactivity in plasma corresponded to intact tracer. The regional first pass extraction fraction of [Brain uptake of [