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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

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.

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.

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.

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.

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.

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.

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.

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.

Fluctuations in blood-oxygenation level dependent (BOLD) signal and perfusion affect the quantification of changes in cerebral blood flow (CBF), coupled to neuronal activity, in arterial spin labeling (ASL). Subtraction methods for control and labeled MR images (i.e. pair-wise, surround subtraction, and subtraction of sinc-interpolated images), postulated to mitigate this interference in pseudo-continuous ASL (pCASL), were evaluated by comparison with quantitative 15O-water PET. At rest, a good agreement in the CBF values was found between PET and MRI for each of the subtraction methods. Stimulation of the visual system resulted in a regional CBF increase in the occipital lobe, which was detectable in both modalities. Bland–Altman analysis showed a systematic underestimation of the CBF values during activation in MRI. Evaluation of the relative CBF change induced by neuronal stimulation showed good inter-modality agreement for the three subtraction methods. Perfusion data obtained with each subtraction method followed the stimulation paradigm without significant differences in the correlation patterns or in the time lag between stimulation and perfusion response. Comparison to the gold standard confirmed the detectability of a neuronal stimulation pattern by pCASL. The results indicate that the combined use of background suppression and short TE reduces the BOLD-weighting in the pCASL signal.

Background The incidence of Alzheimer’s disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Aβ), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk. Methods Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Aβ was measured by 11C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-ε4 carrier status). Results A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p, ALZHEIMERS RESEARCH & THERAPY, 9

A 30-year-old woman presented with a history of generalized tonic-clonic seizures since childhood, occurring for the first time at age 9. The initial diagnostic workup at age 13 demonstrated a distinctive calcified mass of the left frontal lobe on CT (figure, A). Together with a single facial nevus, the lesion was suspected to represent Sturge-Weber-like phakomatosis; however, the patient's clinical history and physical examination failed to reveal further evidence of a neurocutaneous syndrome. Neither MRI nor biopsy for histologic confirmation of the diagnosis was performed. At age 18 the patient was lost to follow-up at the children's hospital.

Aβ deposition is a driving force of Alzheimer's disease pathology and can be detected early by amyloid positron emission tomography. Identifying presymptomatic structural brain changes associated with Aβ deposition might lead to a better understanding of its consequences and provide early diagnostic information. In this respect we analyzed measures of cortical thickness and subcortical volumes along with hippocampal, thalamic and striatal shape and surface area by applying novel analysis strategies for structural magnetic resonance imaging. We included 69 cognitively normal elderly subjects after careful clinical and neuropsychological workup. Standardized uptake value ratios (cerebellar reference) for uptake of 11-C-Pittsburgh Compound B (PiB) were calculated from positron emission tomographic data for a cortical measurement and for bilateral hippocampus, thalamus and striatum. Associations to shape, surface area, volume and cortical thickness were tested using regression models that included significant predictors as covariates. Left anterior hippocampal shape was associated with regional PiB uptake (P 0.05, FDR corrected). Within the entorhinal cortical region of both hemispheres, thickness was negatively associated with cortical PiB uptake (P

Accurate attenuation correction (AC) on PET/MR is still challenging. The purpose of this study was to evaluate the clinical feasibility of AC based on fast zero-echo-time (ZTE) MR imaging by comparing it the default atlas-based AC on a clinical PET/MR scanner. Methods: We recruited 10 patients with malignant diseases not located on the brain. In all patients, a clinically-indicated whole-body 18F-FDG-PET/CT was acquired. In addition, a head PET/MR scan (GE SIGNA TOF-PET/MR) was performed voluntarily. For each patient, two AC maps were generated from the MR images. One was Atlas-AC, derived from T1-weighted LAVA-FLEX images (clinical standard). The other was ZTE-AC, derived from proton-density-weighted ZTE images by applying tissue segmentation and assigning continuous attenuation values to the bone. The AC map generated by PET/CT was used as silver standard. Based on each AC map, PET images were reconstructed from identical raw data on the PET/MR scanner. All PET images were normalized to the SPM5 PET template. After that, these images were qualified visually and quantified in 67 volumes-of-interest (VOIs; automated anatomical labeling (AAL), atlas). Relative differences (%diff) and absolute relative differences (|%diff|) between PET images based on each AC were calculated. FDG uptake in all 670 VOIs and generalized merged VOIs were compared using paired t-test. Results: Qualitative analysis shows that ZTE-AC was robust to patient variability. Nevertheless, misclassification of air and bone in mastoid and nasal areas led the overestimation of PET in the temporal lobe and cerebellum (%diff of ZTE-AC; 2.46±1.19% and 3.31±1.70%, respectively). The |%diff| of all 670 VOIs on ZTE was improved by approximately 25% compared to Atlas-AC (ZTE-AC vs. Atlas-AC; 1.77±1.41% vs. 2.44±1.63%, P < 0.01). In two out of seven generalized VOIs, |%diff| on ZTE-AC were significantly smaller than Atlas-AC (ZTE-AC vs. Atlas-AC; Insula and cingulate, 1.06±0.67% vs. 2.22±1.10%, P < 0.01; central structure, 1.03±0.99% vs. 2.54±1.20%, P < 0.05). Conclusion: The ZTE-AC could provide more accurate AC than clinical Atlas-AC by improving the estimation of head skull attenuation. The misclassification in mastoid and nasal areas must be addressed to prevent the overestimation of PET in regions near the skull base.

Kinetic modeling of PET data derived from mouse models remains hampered by the technical inaccessibility of an accurate input function (IF). In this work, we tested the feasibility of IF measurement with an arteriovenous shunt and a coincidence counter in mice and compared the method with an image-derived IF (IDIF) obtained by ensemble-learning independent component analysis of the heart region.(18)F-FDG brain kinetics were quantified in 2 mouse strains, CD1 and C57BL/6, using the standard 2-tissue-compartment model. Fits obtained with the 2 IFs were compared regarding their goodness of fit as assessed by the residuals, fit parameter SD, and Bland-Altman analysis.On average, cerebral glucose metabolic rate was 10% higher for IDIF-based quantification. The precision of model parameter fitting was significantly higher using the shunt-based IF, rendering the quantification of single process rate constants feasible.We demonstrated that the arterial IF can be measured in mice with a femoral arteriovenous shunt. This technique resulted in higher precision for kinetic modeling parameters than did use of the IDIF. However, for longitudinal or high-throughput studies, the use of a minimally invasive IDIF based on ensemble-learning independent component analysis represents a suitable alternative.

Purpose Reliable 18 F-fluorodeoxyglucose (FDG) uptake quantification is crucial for cancer treatment monitoring. While interobserver variability has been found to be lower for a maximum standard uptake value (SUV) max than for an averaged SUV (SUV mean ), the repeatability has not been investigated yet. In this study, we determined the repeatability of SUV values in two sequential measurements 5 min apart. Methods Positron emission tomography data of malignant chest tumors were acquired dynamically during 45 min in 20 patients. SUV values were derived from the hottest (SUV max ), the mean of the 5 (SUV 5 ) and 10 (SUV 10 ) hottest voxels and the mean of a volume of interest (SUV mean ). The repeatability of the SUV measurements was determined as the standard deviation of the difference between the values at 40 and 45 min and represented as Bland–Altman graphs. Results The standard deviation of the difference between the two sequential scans for SUV max , SUV 5 , SUV 10 and SUV mean was 1.01, 0.53, 0.37 and 0.28. Conclusion The repeatability of SUV is markedly increased by deriving the value from multiple voxels. Compared to SUV max , the variability in SUV measurements is reduced by a factor of 2.7 (2.7=1.01/0.37) if 10 voxels are pooled.

We herein report results of our pilot study using bolus-plus-infusion [11C]raclopride positron emission tomography (PET) scanning to assess endogenous dopamine (DA) release associated with unpredictable monetary rewards in patients with fibromyalgia syndrome (FMS) and healthy controls. The aim of this project was to investigate whether FMS was associated with a dysfunction of the central reward system. Twenty-four women with FMS, based on the American College of Rheumatology classification criteria for FMS, and 17 age-matched healthy women were included in the study. Eleven of the patients with FMS met the DSM-V criteria for major depressive disorder (MDD) [1] (current and past depressive episode). A slot machine task validated by Martin-Soelch et al. [2], which has been shown to reliably induce equilibrium and task-related changes in raclopride binding, was used to measure endogenous DA release in response to unpredictable rewards. PET examinations were performed on a full ring PET/computerized tomography (CT) scanner with a 15.3-cm axial field of view in 3-dimensional mode (Discovery DSTX, GE Healthcare, Waukesha, WI, USA), at the Department of Nuclear Medicine, University Hospital Zurich, Switzerland. The emission data were corrected for attenuation, scatter, random, and dead time using the corresponding CT (120 kV/80 mA), and reconstructed using filtered back projection.

11 C-ABP-688 is a selective tracer for the mGluR5 receptor. Its kinetics is fast and thus favourable for an equilibrium approach to determine receptor-related parameters. The purpose of this study was to test the hypothesis that the pattern of the 11 C-ABP688 uptake using a bolus-plus-infusion (B/I) protocol at early time points corresponds to the perfusion and at a later time point to the total distribution volume. Methods A bolus and a B/I study (1 h each) was performed in five healthy male volunteers. With the B/I protocol, early and late scans were normalized to gray matter, cerebellum and white matter. The same normalization was done on the maps of the total distribution volume (Vt) and K 1 which were calculated in the study with bolus only injection and the Logan method (Vt) and a two-tissue compartment model ( K 1 ). Results There was an excellent correlation close to the identity line between the pattern of the late uptake in the B/I study and Vt of the bolus-only study for all three normalizations. The pattern of the early uptake in the B/I study correlated well with the K 1 maps, but only when normalized to gray matter and cerebellum, not to white matter. Conclusion It is demonstrated that with a B/I protocol the 11 C-ABP688 distribution in late scans reflects the pattern of the total distribution volume and is therefore a measure for the density pattern of mGluR5. The early scans following injection are related to blood flow, although not in a fully quantitative manner. The advantage of the B/I protocol is that no arterial blood sampling is required, which is advantageous in clinical studies.

Purpose: To assess the diagnostic value of O-2-fluoro-18(F)-ethyl-l-tyrosine (18F-FET) positron emission tomography/computed tomography (PET/CT) for patients with advanced head and neck squamous cell carcinoma compared with 18F-fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT at initial staging and following radiochemotherapy. Procedures: Thirteen patients were prospectively enrolled; each of them underwent an 18F-FDG PET/CT and 18F-FET PET/CT before treatment. Ten of those were scanned 10weeks after treatment. Results: Sensitivity, specificity, and accuracy for 18F-FDG PET/CT (primary and lymph node metastases) at initial staging were 89%, 50%, and 81%. For 18F-FET PET/CT the numbers were 70%, 90%, and 74%. Sensitivity, specificity, and accuracy for 18F-FDG PET/CT at follow-up were 71%, 65%, and 67%. For 18F-FET PET/CT the numbers were 29%, 100%, and 83%. Additionally, 18F-FDG PET/CT detected a higher number of second malignancies or distant metastases. Conclusions: 18F-FET is no substitute for 18F-FDG. Although it is more specific, too many malignant lesions are missed due to its lower sensitivity

Noninvasive absolute quantification of cerebral blood flow (CBF) with high spatial resolution is still a challenging task. Arterial spin labeling (ASL) is a promising magnetic resonance imaging (MRI) method for accurate perfusion quantification. However, modeling of ASL data is far from being standardized and has not been investigated in great detail. In this study, two-compartment modeling of monkey ASL data in three physiological conditions (baseline, sensory activated and globally elevated CBF) is reported. Absolute perfusion and arterial transit times were derived for gray matter (GM) and white matter (WM) separately. The uncertainties of the modelamp;amp;lsquo;s result were determined by Monte Carlo simulations. The fitted CBF values for GM were 133 ml/min/100 ml at baseline condition, 165 ml/min/100 ml during visual stimulation and 234 ml/min/100 ml for globally elevated CBF after intravenous injection of acetazolamide. The ratio of GM to WM CBF was 2.5 at baseline and was found to d ecre ase to 1 .6 after application of acetazolamide. The corresponding arterial transit times decreased from 742 to 607 ms in GM and from 985 to 875 ms in WM. Monte Carlo simulations showed that absolute CBF values can be determined with an error of 11–15, while the arterial transit time values have a coefficient of variation of 25–31. With an alternative acquisition scheme, the precision of the arterial transit times can be improved significantly. The CBF values in the occipital lobe of the monkey brain quantified with ASL are higher than previously reported in positron emission tomography studies.

BACKGROUND DOTATATE-based radionuclides have added new options in the diagnosis and treatment of meningiomas; however, a reliable predictor of tumor growth has still not been established. METHODS We analyzed 64 meningiomas imaged with (68)Ga-DOTATATE PET. Tumor growth rates were calculated by volumetric analysis of sequential MRI scans. Maximums of standardized uptake values (SUVmax) were correlated with tumor growth and covariates. RESULTS World Health Organization (WHO) grades I and II meningiomas showed a correlation of SUVmax and tumor growth rate (meningiomas limited to the intracranial compartment: r = 0.757, P < .001, and transosseous growing meningiomas: r = 0.819, P = .024). SUVmax was significantly higher and the slope of the linear regression significantly steeper in transosseous compared with intracranial meningiomas (both P < .001). The association remained significant in multivariate analysis, and the prediction of tumor growth rate was independent of WHO grade. Anaplastic meningiomas showed no significant correlation of SUVmax and tumor growth. CONCLUSIONS (68)Ga-DOTATATE PET is a reliable predictor of tumor growth in WHO grades I and II meningiomas and provides additional information to conventional cross-sectional imaging modalities. Hence, (68)Ga-DOTATATE PET can assist in selecting the time point for treatment initiation. Furthermore, meningiomas with fast tumor growth and transosseous expansion elicit the highest DOTATATE binding; therefore, they might be especially suited for DOTATATE-based therapy.

Attenuation correction (AC) for integrated PET/MR imaging in the human brain is still an open problem. In this study, we evaluated a simplified atlas-based AC (Atlas-AC) by comparing (18)F-FDG PET data corrected using either Atlas-AC or true CT data (CT-AC).We enrolled 8 patients (median age, 63 y). All patients underwent clinically indicated whole-body (18)F-FDG PET/CT for staging, restaging, or follow-up of malignant disease. All patients volunteered for an additional PET/MR of the head (additional tracer was not injected). For each patient, 2 AC maps were generated: an Atlas-AC map registered to a patient-specific liver accelerated volume acquisition-Flex MR sequence and using a vendor-provided head atlas generated from multiple CT head images and a CT-based AC map. For comparative AC, the CT-AC map generated from PET/CT was superimposed on the Atlas-AC map. PET images were reconstructed from the list-mode raw data from the PET/MR imaging scanner using each AC map. All PET images were normalized to the SPM5 PET template, and (18)F-FDG accumulation was quantified in 67 volumes of interest (VOIs; automated anatomic labeling atlas). Relative difference (%diff) between images based on Atlas-AC and CT-AC was calculated, and averaged difference images were generated. (18)F-FDG uptake in all VOIs was compared using Bland-Altman analysis.The range of error in all 536 VOIs was -3.0%-7.3%. Whole-brain (18)F-FDG uptake based on Atlas-AC was slightly underestimated (%diff = 2.19% ± 1.40%). The underestimation was most pronounced in the regions below the anterior/posterior commissure line, such as the cerebellum, temporal lobe, and central structures (%diff = 3.69% ± 1.43%, 3.25% ± 1.42%, and 3.05% ± 1.18%), suggesting that Atlas-AC tends to underestimate the attenuation values of the skull base bone.When compared with the gold-standard CT-AC, errors introduced using Atlas-AC did not exceed 8% in any brain region investigated. Underestimation of (18)F-FDG uptake was minor (4%) but significant in regions near the skull base.

To present our clinical experience in terms of disease presentation and choice of revascularisation procedure in our first group of 23 European Moyamoya angiopathy (disease and syndrome) patients. METHOD AND PATIENT SELECTION: Twenty three patients were diagnosed and treated from 1997-2001 in our neurosurgical department. All patients underwent preoperative angiography, colour Doppler examination, cranial MRI and/or CT scans, HMPAO-SPECT or H(2)(15)O PET (baseline and Diamox challenge) scans. Nineteen patients presented with child-juvenile Moyamoya angiopathy with an average age at presentation of 8 years (range 1-17 years), in 4 patients adult Moyamoya was diagnosed with a mean age at presentation of 34 years (range 23-40 years).In all but one patient bilateral affection was present at the time of diagnosis. All patients underwent direct and/or additional indirect revascularisation procedures. Twenty-one patients underwent bilateral revascularisation procedures. In two patients a unilateral procedure was performed. A direct STA-MCA bypass (superficial temporal artery branch - middle cerebral artery branch anastomosis) was performed in all patients. Additional direct STA-ACA bypass (STA - anterior cerebral artery branch anastomosis) was performed in 10 patients. Indirect arteriosynangiosis using the occipital artery was performed in the posterior cerebral artery (PCA) territory in 3 patients. The frontal branch of the STA was used for arteriosynangiosis in the frontal region in another 2 patients. Indirect frontal durasynangiosis was performed in 14 patients. The number and location of multiple revascularisation procedures was determined according to the angiographic findings as well as the site of decreased perfusion reserves seen on H(2)(15)O PET. A one stage revascularisation procedure was performed in 7 patients. Fourteen patients underwent two stage procedures. Following operation no complications were encountered in all but one adult patient who died postoperatively due to a massive middle cerebral artery infarct on the nonoperated side.As territorial hemodynamic disorder seems to be a characteristic in Moyamoya disease and/or syndrome, judging from our experience with European patients in our series, and several reports hitherto, treatment with multiple revascularisation procedures is considered to be justified.

We tested the prediction that single photon emission computed tomography (SPECT) of the blood flow distribution in speech-activated brain identifies the language-dominant hemisphere. We based the prediction on the hypothesis that language activation leads to focally increased regional cerebral blood flow (rCBF), which is reflected in the uptake of a flow tracer recorded by SPECT. We compared the results of speech activation to the results of functional transcranial Doppler (fTCD) monitoring in the same subjects. Preoperatively, 17 patients (10 women and 7 men with a mean age of 36 +/- 15 years) with diagnoses of epilepsy (n = 14) or arteriovenous malformation (AVM) (n = 3) had two SPECT and two stereo-TCD monitoring studies in each case, one at rest, and one during 3 min of speech activation. Except for two left-handed patients with right-hemisphere dominance, the subjects had the highest changes of rCBF from baseline to activation in the left posterior inferior frontal cortex and in contralateral cerebellum. The results show that changes of the level of neuronal activity reflected by the measurement of rCBF variations might be detected by SPECT. Additionally, the evaluation of hemispheric language dominance based on SPECT showed a complete agreement with the evaluation based on fTCD results (yielding a kappa coefficient equal to 1), and therefore, speech-activation SPECT mapping might be helpful in the evaluation of hemispheric language dominance, especially when fMRI and PET are not available or they are contraindicated for some reason.

Usage of mobile phones is rapidly increasing, but there is limited data on the possible effects of electromagnetic field (EMF) exposure on brain physiology. We investigated the effect of EMF vs. sham control exposure on waking regional cerebral blood flow (rCBF) and on waking and sleep electroencephalogram (EEG) in humans. In Experiment 1, positron emission tomography (PET) scans were taken after unilateral head exposure to 30-min pulse-modulated 900 MHz electromagnetic field (pm-EMF). In Experiment 2, night-time sleep was polysomnographically recorded after EMF exposure. Pulse-modulated EMF exposure increased relative rCBF in the dorsolateral prefrontal cortex ipsilateral to exposure. Also, pm-EMF exposure enhanced EEG power in the alpha frequency range prior to sleep onset and in the spindle frequency range during stage 2 sleep. Exposure to EMF without pulse modulation did not enhance power in the waking or sleep EEG. We previously observed EMF effects on the sleep EEG (A. A. Borbély, R. Huber, T. Graf, B. Fuchs, E. Gallmann and P. Achermann. Neurosci. Lett., 1999, 275: 207-210; R. Huber, T. Graf, K. A. Cote, L. Wittmann, E. Gallmann, D. Matter, J. Schuderer, N. Kuster, A. A. Borbély, and P. Achermann. Neuroreport, 2000, 11: 3321-3325), but the basis for these effects was unknown. The present results show for the first time that (1) pm-EMF alters waking rCBF and (2) pulse modulation of EMF is necessary to induce waking and sleep EEG changes. Pulse-modulated EMF exposure may provide a new, non-invasive method for modifying brain function for experimental, diagnostic and therapeutic purposes.

Background Quantitative measures of 11C-raclopride receptor binding can be used as a correlate of postsynaptic D2 receptor density in the striatum, allowing 11C-raclopride positron emission tomography (PET) to be used for the differentiation of Parkinson’s disease from atypical parkinsonian syndromes. Comparison with reference values is recommended to establish a reliable diagnosis. A PET template specific to raclopride may facilitate direct computation of parametric maps without the need for an additional MR scan, aiding automated image analysis. Methods Sixteen healthy volunteers underwent a dynamic 11C-raclopride PET and a high-resolution T1-weighted MR scan of the brain. PET data from eight healthy subjects was processed to generate a raclopride-specific PET template normalized to standard space. Subsequently, the data processing based on the PET template was validated against the standard magnetic resonance imaging (MRI)-based method in 8 healthy subjects and 20 patients with suspected parkinsonian syndrome. Semi-quantitative image analysis was performed in Montreal Neurological Institute (MNI) and in original image space (OIS) using VOIs derived from a probabilistic brain atlas previously validated by Hammers et al. (Hum Brain Mapp, 15:165–174, 2002). Results The striatal-to-cerebellar ratio (SCR) of 11C-raclopride uptake obtained using the PET template was in good agreement with the MRI-based image processing method, yielding a Lin’s concordance coefficient of 0.87. Bland-Altman analysis showed that all measurements were within the ±1.96 standard deviation range. In all 20 patients, the PET template-based processing was successful and manual volume of interest optimization had no further impact on the diagnosis of PD in this patient group. A maximal difference of

We report the magnetic resonance imaging and proton magnetic resonance spectroscopic findings ((1)HMRS) in a patient with a focal cortical dysgenesis in the right superior frontal gyrus during intermittent frontal status epilepticus (IFSE) with simple partial seizures, and after she had become seizure free. During the status epilepticus, demonstrated by simultaneous behavioural and electroencephalographic telemetric long-term monitoring with scalp electrodes and ictal SPECT, we performed a single voxel spectroscopy of the dysgenic cortex. The(1)HMRS was repeated after 20 days when the patient's seizures were controlled. The N-acetyl-aspartate concentration in the focal dysgenic cortex was decreased in the interictal state but more during IFSE. The creatine/phosphocreatine concentration was normal in both instances. There was a clear lactate signal during IFSE, which was no longer visible in the interictal state. To our knowledge this is the first report of a(1)HMRS study of a focal cortical dysgenesis during an intermittent status epilepticus. We interpret the observed changes as signs of histopathological changes inherent to a cortical malformation and of an impaired energy metabolism due to the partial status epilepticus.

To study the role of GABA-ergic mechanisms in sleep regulation, the combined action of 40 h sleep deprivation and either 20 mg zolpidem or placebo on the sleep electroencephalogram (EEG) were investigated by quantitative EEG analysis in eight young men who participated in a positron emission tomography study. Compared with baseline, sleep deprivation increased low-frequency (1.25-7.0 Hz) EEG power in non-rapid eye movement (NREM) sleep in the placebo night. After administration of zolpidem, power in the 3.75-10.0 Hz range and 14. 25-16.0 Hz band was reduced. The largest decrease was observed in the theta band. Comparison with placebo revealed that zolpidem attenuated power in the entire 1.75-11.0 Hz range. The plasma concentration of zolpidem at 4.5 h after intake showed a positive correlation with the drug-induced difference in power from placebo in the 14.25-16.0 Hz band. Regional EEG analysis based on bipolar derivations along the antero-posterior axis disclosed, for NREM sleep, a drug-induced posterior shift of power in the frequency range of 7.75-9.75 Hz. Zolpidem did not affect rapid eye movemnt sleep spectra. We conclude that sleep deprivation and agonistic modulation of GABAA receptors have separate and additive effects on power spectra and that their effects are mediated by different neurophysiological mechanisms.

There is a need for a quantitative myocardial perfusion agent that does not require an on-site cyclotron. Early studies with manganese demonstrated that this trace metal is of potential use for myocardial imaging. 52mMn can be produced in a 52Fe-52mMn generator and is suitable for positron emission tomographic (PET) imaging. The purpose of this study was to evaluate 52mMn with regard to its potential to quantitatively assess myocardial perfusion. Dynamic PET imaging was performed in six pigs with various doses of dipyridamole to increase blood flow. Retention (R) and model-based K1 values were correlated with microsphere blood flow. The models consisted of one (K1, k2) and two (K1, k2, k3) tissue compartments. Anterior, lateral and septal regions showed a good myocardium-to-background ratio; the evaluation of the inferior wall was impaired by high liver uptake. Linear regression yielded the following equations: K1=1.152 flow+0.059 (r=0.92), R=0.069 flow+0.034 (r=0.84). Based on these regressions, K1 increased 2.7-fold and R 2.6-fold in the examined flow range of 0.5-2 ml/min/g (fourfold increase), demonstrating an underestimation of higher flow rates by both measures. It is concluded that 52mMn allows the qualitative assessment of myocardial perfusion but does not meet the requirements of a quantitative myocardial perfusion agent.

To evaluate whole-body positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in the detection of metastasis from melanoma.Whole-body PET was performed in 33 patients with either known metastatic or newly diagnosed melanoma. Patients with suspected metastases also underwent computed tomography, magnetic resonance imaging, or both. Diagnoses were confirmed with histologic examination or with at least one imaging modality in addition to PET. Blinded interpretations of PET scans were performed.Forty of 53 lesions evaluated proved to be melanoma metastases. Whole-body PET correctly depicted 37 sites of metastases. Three cutaneous metastases (3 mm) were missed. PET correctly excluded malignancy in 10 cases where suspicious lesions were found with conventional cross-sectional imaging modalities but later ruled out with fine-needle biopsy. In six patients, PET depicted new metastases. The sensitivity for the detection of malignant lesions was 92%; the specificity for reading the PET images without clinical information was 77% and with clinical information was 100%.These results suggest that whole-body FDG PET is an effective imaging modality to screen for metastases from malignant melanoma.

ZusammenfassungIn jüngsten Publikationen wurde die Dopamin-D2-Rezeptorszintigraphie mit Benz-amiden zur spezifischen Darstellung von Melanomen vorgeschlagen. In einer prospektiven Studie wurde die Wertigkeit von 123I-Jodbenzofuran (IBF), einem hochspezifischen und hochaffinen Dopamin-D2-Rezeptorliganden zum Nachweis von Melanommetastasen untersucht. Mit der IBF-D2-Rezeptorszintigraphie ließen sich nur 2 von 17 Melanommetastasen nachweisen. Die Beurteilung des Abdomens war durch die hepatobiliäre Ausscheidung des Radionuklids stark eingeschränkt. Der Quotient Striatum/Frontalhirn von 2,75 ± 0,49 3 h p.i. belegte die hohe D2-Rezeptorbindung des Liganden. Die IBF-D2-Rezeptorszintigraphie ist als Staginguntersuchung beim Melanom nicht geeignet.

One of the advantages of positron emission tomography (PET) is the possibility of calculating quantitative values for all kinds of parameters, such as glucose metabolism, receptor densities, blood flow, and many other parameters.

Positron emission tomography-derived 11C-labeled acetate kinetics have been shown to reflect myocardial oxidative metabolism. The objective of the study was to use this metabolic imaging technique in combination with an evaluation of left ventricular work as an index of ventricular mechanical efficiency.The effects of ventricular ejection fraction and loading on this index were studied quantitatively in a canine experimental model. There was a curvilinear relationship between efficiency and the end-diastolic volume per unit mass (r = 0.84), which appeared to integrate the main determinants of left ventricular mechanical performance successfully and allowed the detection of a decreased ventricular efficiency in acute experimental heart failure.This approach appears to have the potential to assess the energetic working point of the ventricle in clinical heart disease and follow the effects of therapy. The data demonstrate the feasibility of an estimate of ventricular efficiency that relies on noninvasive data-acquisition techniques.

In nocturnal frontal lobe epilepsy (NFLE), seizures occur almost exclusively during NREM sleep. Why precisely these seizures are sleep-bound remains unknown. Studies of patients with nonlesional familial forms of NFLE have suggested the arousal system may play a major role in their pathogenesis. We report the case of a patient with pharmaco-resistant, probably cryptogenic form of non-familial NFLE and strictly sleep-bound seizures that could be elicited by alerting stimuli and were associated with ictal bilateral thalamic and right orbital-insular hyperperfusion on SPECT imaging.Case report.University Hospital Zurich.One patient with pharmaco-resistant epilepsy.This case shows that the arousal system plays a fundamental role also in cryptogenic non-familial forms of NFLE.

Positron emission tomography (PET) has become a very valuable modality to evaluate different aspects of brain tumors. A good summary is given by two recent reviews [1,2]. Simply stated, PET allows the quantitative measurement of radioactivity in a target volume based on the annihilation of positrons. The spatial resolution of state-of-the-art commercial PET scanners is in the order of 4–5 mm. Just as important for tumor evaluation is the tracer used, because it is the nature of the tracer which determines the biological properties of the healthy or diseased tissues that are measured. The useful clinical applications of PET in the evaluation of brain tumors are summarized in Table 1.

(11)C-ABP688 is a new PET ligand to assess the subtype 5 metabotropic glutamate receptor (mGlu(5)). The purpose of this study was to evaluate different methods for the analysis of human (11)C-ABP688 data acquired from 6 healthy, young volunteers.The methods were a 1-tissue-compartment model (K(1), k(2)''), a 2-tissue-compartment model (K1-k4), and the noncompartmental method developed by Logan. Parameters related to receptor density were the total distribution volume (DV), DV'' (= K(1)/k(2)'', 1 tissue compartment); specific DV, DV(C2) (= K(1)/k(2)' x k(3)'/k(4), 2 tissue compartments); and DV(tot) for the noncompartmental method.The 1-tissue-compartment model was too simple to adequately fit the data. DV(C2) calculated with the 2-tissue-compartment model ranged from 5.45 +/- 1.47 (anterior cingulate) to 1.91 +/- 0.32 (cerebellum). The corresponding values for DV(tot), calculated with the 2-tissue-compartment model and the Logan method (in parentheses), were 6.57 +/- 1.45 (6.35 +/- 1.32) and 2.93 +/- 0.53 (2.48 +/- 0.40). There was no clear evidence of a region devoid of mGlu(5) receptors. The first-pass extraction fraction exceeded 95%. The minimal scan duration to obtain stable results was estimated to be 45 min.(11)C-ABP688 displays favorable kinetics for assessing mGlu(5) receptors. For tracer kinetic modeling, 2-tissue-compartment models are clearly superior to models with only 1 tissue compartment. In comparison to the compartmental models, the Logan method is equally useful if only DV(tot) values are required and fast pixelwise parametric maps are desired. The lack of regions devoid of receptors limits the use of reference region methods that do not require arterial blood sampling. Another advantage of the tracer is the fast kinetics that allow for relatively short acquisitions.

European Journal of Nuclear Medicine and Molecular Imaging, 33 (6), ISSN:1619-7070, ISSN:1619-7089

Repetitive transcranial magnetic stimulation (rTMS) is a means to study the function and connectivity of brain areas. The present study addressed the question of hemispheric asymmetry of frontal regions and aimed to further understand the acute effects of high- and low-frequency rTMS on regional cerebral blood flow (rCBF). Sixteen healthy right-handed men were imaged using H(2)(15)O positron emission tomography (PET) immediately after stimulation. High (10 Hz)- and low (1 Hz)-frequency suprathreshold short-duration rTMS was applied over either the left or right dorsolateral prefrontal cortex (DLPFC). Slow and fast rTMS applied over the left DLPFC significantly increased CBF in the stimulated area. Compared to baseline, slow rTMS induced a significant increase in CBF contralateral to the stimulation site, in the right caudate body and in the anterior cingulum. Furthermore, slow rTMS decreased CBF in the orbitofrontal cortex (OFC, ipsilateral to stimulation side). Fast rTMS applied over the right DLPFC was associated with increased activity at the stimulation site, in the bilateral orbitofrontal cortex and in the left medial thalamus compared to 1-Hz rTMS. These results show that rCBF changes induced by prefrontal rTMS differ upon hemisphere stimulated and vary with stimulation frequency. These differential neurophysiological effects of short-train rTMS with respect to side and frequency suggest hemisphere-dependent functional circuits of frontal cortico-subcortical areas.

Brain activation dissociates during the repeated performance of memory tasks with decreasing medial temporal and increasing orbitofrontal activation. The impact of such adaptations on a baseline task is unknown. In this study, we used H 2 15 O positron emission tomography (PET) in two groups of subjects performing a continuous recognition task and a baseline task. The group performing the baseline task after the main task showed significant medial temporal activation in the subtraction (recognition task–baseline). The group performing the baseline task at the beginning showed right orbitofrontal activation. These differences appeared to result primarily from different activations during the baseline task. It thus appears that the temporal context of a baseline task may fundamentally alter cognitive requirements and substantially influence apparent brain activation during a memory task. We suggest that the automatic filtration of memories according to their relevance for ongoing reality, a capacity mediated by the orbitofrontal cortex, is one such influence on apparent activation.

Beta-probes are a relatively new tool for tracer kinetic studies in animals. They are highly suited to evaluate new positron emission tomography tracers or measure physiologic parameters at rest and after some kind of stimulation or intervention. In many of these experiments, the knowledge of CBF is highly important. Thus, the purpose of this study was to evaluate the method of CBF measurements using a beta-probe and H215O. CBF was measured in the barrel cortex of eight rats at baseline and after acetazolamide challenge. Trigeminal nerve stimulation was additionally performed in five animals. In each category, three injections of 250 to 300 MBq H215O were performed at 10-minute intervals. Data were analyzed using a standard one-tissue compartment model (K1 = CBF, k2 = CBF/p, where p is the partition coefficient). Values for K1 were 0.35 ± 0.09, 0.58 ± 0.16, and 0.49 ± 0.03 mL · min−1 · mL−1 at rest, after acetazolamide challenge, and during trigeminal nerve stimulation, respectively. The corresponding values for k2 were 0.55 ± 0.12, 0.94 ± 0.16, and 0.85 ± 0.12 min−7, and for p were 0.64 ± 0.05, 0.61 ± 0.07, and 0.59 ± 0.06. The standard deviation of the difference between two successive experiments, a measure for the reproducibility of the method, was 10.1%, 13.0%, and 5.7% for K1, k2, and p, respectively. In summary, beta-probes in conjunction with H215O allow the reproducible quantitative measurement of CBF, although some systematic underestimation seems to occur, probably because of partial volume effects.

A successful strategy to memorize unrelated items is to associate them semantically. This learning method is typical for declarative memory and depends on the medial temporal lobe (MTL). Yet, only a small fraction of perceived items emerge into conscious awareness and receive the status of representations in declarative memory. This functional magnetic resonance imaging (fMRI) study tackled the mnemonic fate of unrelated item pairs processed without conscious awareness. Stimuli consisted of a face and a written profession (experimental condition) or of a face (control condition) exposed very briefly between pattern masks. Although the participants were unaware of the stimuli, activity in the hippocampus and perirhinal cortex was changed in the experimental versus the control condition; perirhinal activity changes correlated with the reaction time measure of the later nonconscious retrieval. For retrieval, the previously presented faces were shown again, this time for conscious inspection. The task was to guess the professional category of each face. This task was to induce a nonconscious retrieval of previously formed face-profession associations. Remarkably, activity in the hippocampus and perirhinal cortex was enhanced when subjects were confronted with faces from the experimental versus the control condition. The degree of hippocampal and perirhinal activation changes correlated with the reaction time measure of nonconscious retrieval. Together, our findings suggest that new semantic associations can be formed and retrieved by way of the medial temporal lobe without awareness of the associations or its components at encoding or any awareness that one is remembering at retrieval.

The hippocampal formation is known for its importance in conscious, declarative memory. Here, we report neuroimaging evidence in humans for an additional role of the hippocampal formation in nonconscious memory. We maskedly presented combinations of faces and written professions such that subjects were not aware of them. Nevertheless, the masked presentations activated many of the brain regions that unmasked presentations of these stimuli did. To induce a nonconscious retrieval of the faces and face-associated occupational information, subjects were instructed to view the previously masked faces and to guess the professional category of each person--academic, artist, and workman. Guessing the professional category of previously masked versus new faces activated the left and right hippocampal formation and right perirhinal cortex as well as bilateral fusiform areas and fronto-temporal areas known to mediate the retrieval of semantic information. These activations within the semantic processing system suggest that conceptual knowledge acquired during masking was nonconsciously retrieved. Our data provide clues to an analogous role of the hippocampus in conscious and nonconscious memory.

The quantitative determination of regional cerebral blood flow (rCBF) is important in certain clinical and research applications. The disadvantage of most quantitative methods using H(2)(15)O positron emission tomography (PET) is the need for arterial blood sampling. In this study a new non-invasive method for rCBF quantification was evaluated. The method is based on the washout rate of H(2)(15)O following intravenous injection. All results were obtained with Alpert's method, which yields maps of the washin parameter K(1) (rCBF(K1)) and the washout parameter k(2) (rCBF(k2)). Maps of rCBF(K1) were computed with measured arterial input curves. Maps of rCBF(k2*) were calculated with a standard input curve which was the mean of eight individual input curves. The mean of grey matter rCBF(k2*) (CBF(k2*)) was then compared with the mean of rCBF(K1) (CBF(K1)) in ten healthy volunteer smokers who underwent two PET sessions on day 1 and day 3. Each session consisted of three serial H(2)(15)O scans. Reproducibility was analysed using the rCBF difference scan 3-scan 2 in each session. The perfusion reserve (PR = rCBF(acetazolamide)-rCBF(baseline)) following acetazolamide challenge was calculated with rCBF(k2*) (PR(k2*)) and rCBF(K1) (PR(K1)) in ten patients with cerebrovascular disease. The difference CBF(k2*)-CBF(K1) was 5.90+/-8.12 ml/min/100 ml (mean+/-SD, n=55). The SD of the scan 3-scan 1 difference was 6.1% for rCBF(k2*) and rCBF(K1), demonstrating a high reproducibility. Perfusion reserve values determined with rCBF(K1) and rCBF(k2*) were in high agreement (difference PR(k2*)-PR(K1)=-6.5+/-10.4%, PR expressed in percentage increase from baseline). In conclusion, a new non-invasive method for the quantitative determination of rCBF is presented. The method is in good agreement with Alpert's original method and the reproducibility is high. It does not require arterial blood sampling, yields quantitative voxel-by-voxel maps of rCBF, and is computationally efficient and easy to implement.