Synthesis of protectin D1 analogs: novel pro-resolution and radiotracer agents.

Protectin D1 is a specialized pro-resolving mediator with potent pro-resolving and anti-inflammatory effects in vivo in several human disease models. Herein the preparation of the first synthetic analog of protectin D1, named 22-F-PD1, is presented together with data from in vivo investigations. This analog showed potent pro-resolving and anti-inflammatory properties. These results inspired the preparation of the radiotracer 22-[18F]F-PD1-ME that was used in a positron emission tomography proof of concept study. Altogether, the findings presented contribute to new knowledge on the biomolecular properties of protectin D1 analogs. In addition, an improved formal synthesis of the metabolite 22-OH-PD1 is reported.

Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2.

Sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA)2 transports Ca2+ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca2+ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca2+ handling in the cardiomyocyte. Previous studies using cardiomyocyte-specific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca2+ transient amplitude and induces compensatory Ca2+ transport mechanisms that may lead to more inefficient Ca2+ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MVo2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca2+ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MVo2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, work-dependent MVo2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modeling-based studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction.

Morphometric changes in the episodic memory network and tau pathologic features correlate with memory performance in patients with mild cognitive impairment.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) may affect several cognitive domains, including attention and reasoning, but is often first characterized by memory deficits. The purpose of this study was to ask these 2 questions: 1) Can levels of CSF tau proteins and amyloid beta 42 peptide explain thinning of the cerebral cortex in patients with MCI? 2) How are brain morphometry, CSF biomarkers, and apolipoprotein E (APOE) allelic variation related to episodic memory function in MCI? MATERIALS AND METHODS: Hippocampal volume and cortical thickness were estimated by MR imaging and compared for patients with MCI (n = 18) and healthy controls (n = 18). In addition, regions of interest (ROIs) were selected in areas where the MCI group had atrophy and which overlapped with the episodic memory network (temporal, entorhinal, inferior parietal, precuneus/posterior cingulate, and frontal). Relationships among morphometry, CSF biomarkers, APOE, and memory were tested. The analyses were repeated with an independent sample of patients with MCI (n = 19). RESULTS: Patients with MCI and pathologic CSF values had hippocampal atrophy. However, both patients with pathologic and patients with nonpathologic CSF had a thinner cortex outside the hippocampal area. CSF pathology was related to hippocampal volume, whereas relationships with cortical thickness were found mainly in one of the samples. Morphometry correlated robustly with memory performance across MCI samples, whereas less stable results were found for tau protein. CONCLUSION: The differences in hippocampal volume between the MCI and the healthy control groups were only found in patients with pathologic CSF biomarkers, whereas differences in cortical thickness were also found for patients without such pathologic features. Morphometry in areas in the episodic memory network was robustly correlated with memory performance. It is speculated that atrophy in these areas may be associated with the memory problems seen in MCI.

A New Method for Radiosynthesis of C-Labeled Carbamate Groups and its Application for a Highly Efficient Synthesis of the Kappa-Opioid Receptor Tracer [C]GR103545.

(11)C-labeled carbamates can be obtained in a three-component coupling reaction of primary or secondary amines with CO(2) and (11)C-methylation reagents. [(11)C]Methyl-triflate mediated methylation of carbamino adducts provides the corresponding (11)C-labeled carbamate groups in excellent yields under mild conditions (temperatures

Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study.

Using PET with the opioidergic ligand [11C]diprenorphine, the authors demonstrate decreased tracer binding in the pineal gland of cluster headache patients vs healthy volunteers. Opioid receptor availability in the hypothalamus and cingulate cortex depended on the duration of the headache disorder. Therefore, the pathophysiology of cluster headache may relate to opioidergic dysfunction in circuitries generating the biologic clock.

Resting state glucose utilization and the CERAD cognitive battery in patients with Alzheimer's disease.

The present study examined the cortical functional representation of neuropsychological domains in Alzheimer's disease (AD) using positron emission tomography (PET) and the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Thirty patients with clinical probable AD and 10 elderly healthy controls underwent (18)FDG brain PET imaging during a resting state. Correlations between metabolic values and cognitive measures were determined using a region of interest analysis with NEUROSTAT (University of Michigan, USA) and a voxel-based analysis with SPM96 (Wellcome Department, London, UK). Specific correlations were seen between measures of episodic memory, verbal fluency and naming and left hemispheric temporal and prefrontal metabolism. Drawing was correlated with metabolism in left prefrontal and left inferior parietal regions. The presented data support the use of metabolic-cognitive correlations to demonstrate the neuronal substrates of cognitive impairment in AD. Subtests of the CERAD battery give a good representation of left, but not of right hemisphere function in AD.

Dose-dependent regional cerebral blood flow changes during remifentanil infusion in humans: a positron emission tomography study.

BACKGROUND: The current study investigated dose-dependent effects of the mu-selective agonist remifentanil on regional cerebral blood flow (rCBF) in volunteers using positron emission tomography (PET). METHODS: Ten right-handed male volunteers were included in a 15O-water PET study. Seven underwent three conditions: control (saline), low remifentanil (0.05 microg x kg(-1) x min(-1)), and moderate remifentanil (0.15 microg x kg(-1) x min(-1)). The remaining three participated in the low and moderate conditions. A semirandomized study protocol was used with control and remifentanil conditions 3 or more months apart. The order of low and moderate conditions was randomized. Cardiovascular and respiratory parameters were monitored. Categoric comparisons between the control, low, and moderate conditions and a pixelwise correlation analysis across the three conditions were performed (P < 0.05, corrected for multiple comparisons) using statistical parametric mapping. RESULTS: Cardiorespiratory parameters were maintained constant over time. At the low remifentanil dose, significant increases in relative rCBF were noted in the lateral prefrontal cortices, inferior parietal cortices, and supplementary motor area. Relative rCBF decreases were observed in the basal mediofrontal cortex, cerebellum, superior temporal lobe, and midbrain gray matter. Moderate doses further increased rCBF in mediofrontal and anterior cingulate cortices, occipital lobe transition, and caudal periventricular grey. Significant decreases were detected in the inferior parietal lobes. These dose-dependent effects of remifentanil on rCBF were confirmed by a correlation analysis. CONCLUSION: Remifentanil induced dose-dependent changes in relative rCBF in areas involved in pain processing. At moderate doses, rCBF responses were additionally detected in structures known to participate in modulation of vigilance and alertness. Insight into the mechanisms of opioid analgesia within the pain-processing neural network may lead to a better understanding of antinociception and opioid treatment.

Statistical brain mapping of 18F-FDG PET in Alzheimer's disease: validation of anatomic standardization for atrophied brains.

UNLABELLED: Despite the increased use of statistical mapping to detect brain functional changes in Alzheimer's disease (AD), potential artifacts introduced by stereotactic anatomic standardization of atrophied brains have not been examined carefully. We investigated the effects of anatomic standardization by Statistical Parametric Mapping (SPM) and NEUROSTAT. METHODS: First, 10 AD patients and 10 age-matched healthy volunteers underwent 18F-FDG brain PET imaging. Each image set was standardized to a stereotactic brain template using SPM or NEUROSTAT, followed by pixel normalization to the global or cerebellar activity. Within-group comparisons of standardized image sets by each method and a between-group comparison of healthy volunteers and AD patients were performed using the statistical analysis routines of SPM. Second, simulated PET image sets were generated from segmented MR image sets of 5 healthy volunteers and 5 AD patients. Using the anatomic standardization parameters estimated on the simulated image sets, original gray matter MR image sets were transformed to the stereotactic coordinate system. Between-group subtraction analyses of the transformed gray matter image sets between healthy volunteers and AD groups were performed to examine the accuracy of cortical gray matter matching. RESULTS: Between-group comparison by SPM or NEUROSTAT showed generally similar areas of hypometabolism in bilateral temporoparietal, posterior cingulate, and left frontal cortices. Both methods showed possible deformation artifacts in the anterior part of the corpus callosum. The localization of the peak hypometabolism varied considerably between the two methods when global normalization was applied. The use of a common brain template for standardization resulted in asymmetric differences in cortical margins, indicating systematic differences in the deformation algorithms. The realistic simulation study revealed gray matter mismatches to be 20% greater with SPM than with NEUROSTAT. CONCLUSION: Although different statistical mapping methods may yield grossly similar patterns of hypometabolism in AD, the extent, severity, and peak location of metabolic changes can be inconsistent. Deformation accuracy appears to be more prone to atrophy. These limitations need to be considered carefully in the application and interpretation of brain mapping analysis in atrophied brains.

Neurophysiological processes underlying the phantom limb pain experience and the use of hypnosis in its clinical management: an intensive examination of two patients.

In a pilot study with 2 patients suffering from phantom limb pain (PLP), hypnotic suggestions were used to modify and control the experience of the phantom limb, and positron emission tomography (PET) was used to index underlying pathways and areas involved in the processing of phantom limb experience (PLE) and PLP. The patients' subjective experiences of pain were recorded in a semistructured protocol. PET results demonstrated activation in areas known to be responsible for sensory and motor processing. The reported subjective experiences of PLP and movement corresponded with predicted brain activity patterns. This work helps to clarify the central nervous system correlates of phantom limb sensations, including pain. It further suggests that hypnosis can be incorporated into treatment protocols for PLP.

Activation of frontal premotor areas during suprathreshold transcranial magnetic stimulation of the left primary sensorimotor cortex: a glucose metabolic PET study.

We employed cerebral (18)Fluoro-deoxyglucose positron emission tomography ([(18)F]FDG-PET) to visualize neuronal activation of the frontal motor and premotor cortex during suprathreshold repetitive transcranial magnetic stimulation (rTMS) applied to the left primary sensorimotor hand area (SM1(HAND)). Twelve right-handed normal subjects underwent two [(18)F]FDG-PET measurements at baseline without rTMS and during suprathreshold 2 Hz rTMS of the left SM1(HAND). In the rTMS condition, 1,800 magnetic stimuli at an intensity of 140% of motor-resting threshold were delivered immediately after intravenous injection of [(18)F]FDG. Relative differences in the normalized regional cerebral metabolic rate for glucose (rCMRglc) between the rTMS condition and baseline were determined using a voxel-by-voxel Student's t-test and a volume-of-interest analysis. Data analysis was a priori restricted to primary motor and premotor areas in the frontal cortex, namely the SM1, the supplementary motor area (SMA), the lateral premotor cortex (PMC), and the caudal anterior cingulate cortex (ACC) of either hemisphere. In addition to a relative increase in normalized rCMRglc in the stimulated SM1(HAND), suprathreshold rTMS was associated with well-localized increases in normalized rCMRglc in the caudal SMA and ACC on the medial wall of the frontal cortex and in the right precentral gyrus in the lateral PMC rostrally to the SM1. These data demonstrate that a selective activation of the SM1(HAND) is paralleled by an activation of a distinct set of remote premotor areas, suggesting a functional interaction between the primary motor and premotor cortex in humans.

Phantom limb pain in the human brain: unraveling neural circuitries of phantom limb sensations using positron emission tomography.

Pain and other phantom limb (PL) sensations have been proposed to be generated in the brain and to be reflected in activation of specific neural circuits. To test this hypothesis, hypnosis was used as a cognitive tool to alternate between the sensation of PL movement and pain in 8 amputees. Brain activity was measured using positron emission tomography. PL movement and pain were represented by a propagation of neuronal activity within the corresponding sensorimotor and pain-processing networks. The sensation of movement was significantly (corrected for multiple comparisons) related to activity in the supplementary motor area and the primary sensorimotor cortex. The sensation of a painful PL posture activated the same brain areas but was weaker and less extended in the supplementary motor area. In contrast to the sensation of movement, pain was significantly related to activity in the thalamus, anterior cingulate, and lateral prefrontal cortex. Subjectively rated PL pain sensation correlated positively to activations in the anterior and posterior cingulate. These findings provide evidence that PL sensations are produced by the same central nervous processes that underlie the experience of the body when it is intact and that the corporeal awareness of PL pain is encoded in a thalamocortical network.

6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine ([18F]DPN): synthesis, biologic evaluation, and comparison with [11C]DPN in humans.

UNLABELLED: 6-O(2-[18F]fluoroethyl)-6- -desmethyldiprenorphine ([18F]DPN) was developed and biologically evaluated. Results of animal experiments, binding studies in vivo, and a human PET study are reported and compared with those of [11C]DPN. METHODS: [18F]DPN was obtained by 18F-fluoroethylation of 3-O-trityl-6-O-desmethyldiprenorphine and subsequent deprotection in good radiochemical yields (23% +/- 7%; 100 min; 37 TBq/mmol). Binding of [18F]DPN to mu, kappa, and delta opioid receptors was shown by autoradiography studies on rat brain slices. Quantification of cerebral opioid receptor binding in men was performed by spectral analysis of a dynamic PET scan (25 frames, 90 min) after intravenous application of 63 MBq [18F]DPN (36 GBq/micromol) and correction for metabolites. RESULTS: [18F]DPN shows high affinity to opioid receptors. Parametric images (impulse response function at 60 min) of this human study showed a binding pattern of [18F]DPN equal to that of a control group (n = 9 healthy volunteers) after administration of [11C]DPN. CONCLUSION: The advantage of the longer half-life of 18F will allow extended scanning periods, more flexible interventions (e.g., displacement studies), and DPN to be available to PET centers without an on-site cyclotron.

Lasting cortical activation after repetitive TMS of the motor cortex: a glucose metabolic study.

OBJECTIVE: Cerebral [18F]fluorodeoxy-D-glucose PET ([18F]FDG-PET) was used to visualize the lasting neuronal activation after repetitive transcranial magnetic stimulation (rTMS) over the left hand area of the primary motor cortex (M1HAND). BACKGROUND: Applied over M1HAND, rTMS has been shown to produce a modulation of corticomotor excitability beyond the time of stimulation itself. METHODS: Eight right-handed subjects underwent nonquantitative [18F]FDG-PET measurements during two experimental conditions: at rest and after focal subthreshold 5-Hz rTMS over the left M1HAND. In the post-rTMS condition, [18F]FDG was injected immediately after the administration of 1,800 magnetic pulses over the left M1HAND. Relative differences in normalized regional cerebral metabolic rate of glucose (normalized rCMRglc) between conditions were determined using a voxel-by-voxel Student's t-test and volume-of-interest (VOI) analysis. Analysis was a priori restricted to the M1HAND, the supplementary motor area (SMA), and the primary auditory cortex of both hemispheres. RESULTS: A 5-Hz rTMS of the left M1HAND caused a lasting relative increase in normalized rCMRglc within the M1HAND bilaterally and the SMA. The magnitude and the topographic pattern of persisting relative rCMRglc increases within these motor cortical areas demonstrated considerable interindividual variations. CONCLUSIONS: Subthreshold 5-Hz repetitive transcranial magnetic stimulation (rTMS) over the hand area of the primary motor cortex is associated with a persisting neuronal activation in a distinct set of motor cortical areas beyond the time of stimulation. The current findings demonstrate that [18F]FDG-PET can localize and quantify regional net changes in synaptic cortical activity after rTMS and thus might elucidate the mechanisms underlying rTMS-associated therapeutic effects.

Metabolic activity changes in the rat spinal cord during adjuvant monoarthritis.

The development of chronic pain is associated with activity-dependent plastic changes in neuronal structures in the peripheral and central nervous system. In order to investigate the time-dependent processing of afferent noxious stimuli in the spinal cord we employed the quantitative autoradiographic 2-deoxyglucose technique in a model of chronic monoarthritic pain in the rat. Spinal metabolic activity was determined at various time-points (two, four and 14 days) after the injection of complete Freund's adjuvant into the left tibiotarsal joint. In addition, the effect of acute noxious mechanical stimulation of the arthritic joint was investigated at 14 days of monoarthritis. Local glucose utilization was determined in lumbar segments L2-L5, ipsi- and contralateral to the inflamed hindpaw, and compared with saline-injected controls. In general, monoarthritic animals had bilaterally increased metabolic activity in all laminae of the spinal cord. Detailing the time-course showed that in rats with two days of monoarthritis metabolic activity was significantly increased to a similar extent on both sides of all spinal laminae. In contrast, at four days, glucose utilization in deep laminae of the dorsal horn (laminae V-VI), the central gray area (laminae X) and the ventral horn (laminae VII-IX) tended to return to control levels. At 14 days of monoarthritis, however, metabolic activity showed a further increase in all laminae of the spinal cord. This increase was more pronounced on the side ipsilateral to inflammation, reaching 65% above corresponding control levels in laminae V, VI. Animals with 14 days of monoarthritis which were subjected to mechanical noxious stimulation of the arthritic joint displayed clear behavioral signs of acute pain. Although in this group metabolic activity was above control levels, it was lower than in animals with 14 days of monoarthritis that were not additionally stimulated. The data show not only a general increase of spinal cord metabolic activity during the time-course of the development of a chronic pain state, but also show a region-specific non-linear time profile. This may reflect the complexity of transducing and suppressive transmitter systems involved in the central processing of ongoing pain.

Imaging functional activation of the auditory cortex during focal repetitive transcranial magnetic stimulation of the primary motor cortex in normal subjects.

Positron emission tomography (PET) during focal repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising approach to study cortical connectivity in awake humans. However, the noise caused by the discharging magnetic coil might have confounding effects on the rTMS-related cortical activation pattern. In twelve healthy volunteers, 18-fluoro-2-deoxy-D-glucose (18FDG) PET was employed to visualize the functional activation of the primary auditory cortex (PAC) during 2 Hz rTMS of the left primary sensorimotor hand area. Magnetic stimuli (1800) were applied at an intensity of 140% of motor resting threshold during the uptake period of 18FDG. Though all subjects wore earplugs, rTMS-related noise induced a consistent bilateral increase of regional glucose utilization in the PAC (P < 0.05, corrected). Thus, rTMS-related acoustic input needs to be taken into account in combined rTMS/PET studies.

Central pain after pontine infarction is associated with changes in opioid receptor binding: a PET study with 11C-diprenorphine.

Using 18F-fluorodeoxyglucose and 11C-diprenorphine positron emission tomography (PET), we investigated alterations in glucose metabolism and opioid receptor binding in a patient with central poststroke pain, which developed after a small pontine hemorrhagic infarction. In comparison with normal databases, reduced 11C-diprenorphine binding was more accentuated than the hypometabolism on the lateral cortical surface contralateral to the symptoms, and a differential abnormal distribution between the tracers was seen in pain-related central structures. These results show that 11C-diprenorphine PET provides unique information for the understanding of central poststroke pain.

Opioid receptors in the human cerebellum: evidence from [11C]diprenorphine PET, mRNA expression and autoradiography.

Little is known regarding opioid receptors in the human cerebellum. The present [11C]diprenorphine PET study investigated opioid receptor binding in the human cerebellum in vivo, and showed a differential binding level in cerebellar cortex, vermis and dentate nuclei. The additional study in vitro of opioid receptors in human cerebellar cortex and rat brain corroborated the presence of opioidergic mechanisms in the human cerebellum in contrast to the rat. A differential cellular distribution pattern was detected for the three major opioid receptors investigated. For the mu-receptor, and at a lower level for the kappa-receptor, mRNA expression was mainly observed over granule cells. Binding sites were most prominent in the molecular layer. For the delta-receptor no signal was detected. The consideration of cerebellar opioidergic mechanisms and the distribution patterns of the various opioid receptors may promote the understanding of cerebellar function and of opioidergic pharmacology in the human.

Region-specific encoding of sensory and affective components of pain in the human brain: a positron emission tomography correlation analysis.

Brain imaging with positron emission tomography has identified some of the principal cerebral structures of a central network activated by pain. To discover whether the different cortical and subcortical areas process different components of the multidimensional nature of pain, we performed a regression analysis between noxious heat-related regional blood flow increases and experimental pain parameters reflecting detection of pain, encoding of pain intensity, as well as pain unpleasantness. The results of our activation study indicate that different functions in pain processing can be attributed to different brain regions; ie, the gating function reflected by the pain threshold appeared to be related to anterior cingulate cortex, the frontal inferior cortex, and the thalamus, the coding of pain intensity to the periventricular gray as well as to the posterior cingulate cortex, and the encoding of pain unpleasantness to the posterior sector of the anterior cingulate cortex.

[Tau protein. A potential biological indicator for early detection of Alzheimer disease]. / Tau-Protein. Ein potentieller biologischer Indikator zur Früherkennung der Alzheimer-Krankheit.

In 40 patients with Alzheimer's disease (AD), in 5 patients with non-AD dementia and in 36 cognitively normal controls the concentration of protein tau was determined in the cerebrospinal fluid (CSF). Of the AD patients, 19 were very mildly demented (MMSE score from 25 to 28). Even in these patients, CSF tau was significantly more elevated than in controls. In the non-AD patients protein tau was less increased. Among the AD patients there was no association between CSF tau and severity of cognitive impairment or deficit in cerebral blood flow, determined by SPECT. Our findings suggest that CSF tau may be elevated even at the predementia stage of AD and be useful as a biological marker for the early recognition of the disease.