Serotonergic neurotransmission in the living human brain: a positron emission tomography study using [¹¹C]dasb and [¹¹C]WAY100635 in young healthy men

The central serotonergic (5-HT) system is closely involved in regulating various mental functions such as mood and emotion. In this system, the serotonin transporter (5-HTT) and the 5-HT(1A) receptor play important roles in the pathophysiology and treatment of mood and anxiety disorders. However, only a few integrated databases have considered the intraindividual relationship between pre- and postsynaptic serotonergic transmission. In the present study, we constructed a database of 5-HTT and 5-HT(1A) receptors using positron emission tomography (PET) with [11C]DASB and [11C]WAY100635, respectively. Seventeen healthy young men participated in this study. After anatomic standardization of original images, BP(ND) was calculated on a voxel-by-voxel basis using reference tissue methods. The highest binding to 5-HTT was observed in the dorsal raphe nucleus, striatum, and thalamus; moderate binding, in the insula and cingulate cortex; and very low binding, in the cerebral neocortex. In contrast, the highest binding to 5-HT(1A) receptors was seen in the hippocampal regions, insula, neocortical regions, and dorsal raphe nucleus, and very low binding was found in the thalamus and basal ganglia. These distribution patterns were in agreement with those reported in human postmortem studies and previous PET investigations. In addition, exploratory analysis indicated significant negative correlations between the BP(ND) values with both radiotracers in certain regions of the brain, such as the cingulate, insula, and frontal, temporal and parietal cortices (Pearson's correlation, P < 0.05). These databases facilitate the understanding of the regional distribution of serotonergic neurotransmission function in the living human brain and the pathophysiology of various neuropsychiatric disorders.     

Test-retest variability of [¹¹C]raclopride-binding potential in nontreatment-seeking alcoholics

Knowledge of the reproducibility of striatal [11C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine (DA) during pharmacological and cognitive challenges. To our knowledge, no baseline test-retest data exist for nontreatment-seeking alcoholics (NTS). We determined the test-retest reproducibility of baseline RAC binding potential (BP(ND) ) in 12 male NTS subjects. Subjects were scanned twice with single-bolus RAC PET on separate days. Striatal RAC BP (BP(ND) ) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis (LGA) with a reference region. Test-retest variability (TRV), % change in BP(ND) between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was ±6.5% and ±7.1% for LGA. Average striatal ICCs were 0.94 for both methods (P < 0.0001). Striatal BP(ND) values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects.     

Brain kinetics of L-[Β-11 C]DOPA in humans studied by positron emission tomography

Summary The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with¹¹ C in the position has been used for positron emission tomography studies of L-DOPA utilization in the brain. The brain uptake and kinetics of L-[¹¹ C]DOPA-derived radioactivity were studied in healthy male volunteers, and the specific utilization, i.e. decarboxylation rate of L-[¹¹ C]DOPA in different brain areas, was quantified using a brain region devoid of specific L-[¹¹C]DOPA utilization as reference. Total uptake of L-[¹¹ C]DOPA-derived radioactivity measured in the brain varied two- to threefold between subjects, with highest radioactivity in the striatal region. Specific utilization of L-[¹¹C]DOPA radioactivity in the striatal region and in the prefrontal cortex varied twofold between subjects. No specific utilization was observed in other regions of the brain. The uptake of radioactivity in the brain increased dose-dependently with the simultaneous administration of unlabelled L-DOPA up to 10 mg. On the other hand, a decrease in brain radioactivity uptake was measured after pretreatment with 1 mg/kg oral L-DOPA, indicating competition for transport across the blood-brain barrier. Benserazide 0.5 mg/ kg orally increased somewhat the radioactivity uptake to the brain. None of these pharmacological perturbations demonstrated any clearcut effect on specific utilization of L-[¹¹C]DOPA. Thus,¹¹C-labelled L-DOPA is introduced as an alternative to the well-established L-6-[¹⁸ F]fluoro-DOPA methodology in clinical studies on brain L-DOPA uptake and dopamine synthesis.A contribution from the Uppsala University PET Center.     

Evaluation of dopamine D₂/₃ specific binding in the cerebellum for the positron emission tomography radiotracer [¹¹C]FLB 457: implications for measuring cortical dopamine release

In a recent positron emission tomography (PET) study, we demonstrated the ability to measure amphetamine‐induced dopamine (DA) release in the human cortex with the DA D_2/3 radioligand [¹¹C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [¹¹C]FLB 457 signal in the cerebellum represents specific binding to D_2/3 receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [¹¹C]FLB 457 binding potential (BP) (BP_ND) would bias cortical DA release measurements. Thus, we evaluated the fractional contribution of specific binding to D_2/3 receptors in the human cerebellum for [¹¹C]FLB 457. Six healthy human subjects (5M/1F) were studied twice with [¹¹C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D_2/3 partial agonist. [¹¹C]FLB 457 distribution volume (V_T) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [¹¹C]FLB 457 V_T following aripiprazole ranged from ?33 to ?42% in the cortical regions of interest (ROIs). The aripiprazole‐induced change in [¹¹C]FLB 457 V_T in three potential reference regions suggests significant specific binding the cerebellum (CER, –17 ± 12%), but not pons (PON, –10 ± 10%) and centrum semiovale (CESVL, –3 ± 12%). Nevertheless, a reanalysis of the published [¹¹C]FLB 457 test–retest and amphetamine studies suggests that the use of the PON V_T and CESVL V_T as an estimate of nonspecific binding to derive [¹¹C]FLB 457 BP_ND in DA release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure DA release in the cortex. D_2/3 blocking studies with aripiprazole and [¹¹C]FLB 457 suggest specific binding to D_2/3 receptors in the cerebellum. These data also suggest that the contribution of specific binding to D_2/3 receptors in the cerebellum is lower than that in the cortical ROIs and that CER V_T is mostly representative of nonspecific binding. Nevertheless, caution is advised when using reference tissue methods that rely solely on the cerebellum signal as an input function to quantify [¹¹C]FLB 457 BP_ND. Synapse, 2011. © 2011 Wiley‐Liss, Inc.     

The value of [18F]-fluorodeoxyglucose–positron emission tomography/CT scanning in the diagnosis of neurosarcoidosis

Sarcoidosis is a granulomatous disease of unknown aetiology which primarily affects the lungs, but can affect other tissues including the central nervous system (CNS). In neurosarcoidodis, the CNS is often the only affected site, which makes a tissue diagnosis difficult. Although a clinical diagnosis of neurosarcoidosis can often be made, the wide range of potential differential diagnoses, including other steroid responsive conditions (such as idiopathic lymphocytic meningitis) means that a confirmed diagnosis is invaluable. This is particularly important because neurosarcoidosis has a poor prognosis and aggressive immunosuppressive treatment is generally recommended. We present a man with clinically suspected neurosarcoidosis where attempts to obtain histological confirmation of the disease through skin and meningeal biopsy was unhelpful, but a lymph node biopsy, directed with the use of [18F]-fluorodeoxyglucose–positron emission tomography/CT scanning was diagnostic.     

Neuroinflammation in bipolar disorder – A [11C]-(R)-PK11195 positron emission tomography study

Background: The “monocyte-T-cell theory of mood disorders” regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [¹¹C]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential focus of neuroinflammation in bipolar disorder. We aim to determine if there is increased [¹¹C]-(R)-PK11195 binding to activated microglia in the hippocampus of patients with bipolar I disorder when compared to healthy controls.Material and methods: Fourteen patients with bipolar I disorder and eleven healthy controls were included in the analyses. Dynamic 60-min PET scans were acquired after the injection of [¹¹C]-(R)-PK11195. All subjects underwent psychiatric interviews as well as an MRI scan, which was used for anatomic co-registration in the data analysis. The data from the PET scans was analyzed with a two-tissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma and blood curve as input.Results: A significantly increased [¹¹C]-(R)-PK11195 binding potential, which is indicative of neuroinflammation, was found in the right hippocampus of the patients when compared to the healthy controls (1.66 (CI 1.45–1.91) versus 1.33 (CI 1.16–1.53); p = 0.033, respectively). Although the same trend was observed in the left hippocampus, this difference was not statistically significant.Conclusion: This study is the first to demonstrate the presence of focal neuroinflammation in the right hippocampus in bipolar I disorder.     

Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [1?F]DPA-714

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Activated microglia/macrophages play a key role in the immunopathogenesis of MS and its corresponding animal models, experimental autoimmune encephalomyelitis (EAE). Microglia activation begins at early stages of the disease and is associated with elevated expression of the 18 kDa mitochondrial translocator protein (TSPO). Thus, positron emission tomography (PET) imaging of microglial activation using TSPO-specific radioligands could be valuable for monitoring disease-associated neuroinflammatory processes. EAE was induced in rats using a fragment of myelin basic protein, yielding acute clinical disease that reflects extensive spinal cord inflammation. Enhanced TSPO expression in spinal cords of EAE rats versus those of controls was confirmed by Western blot and immunohistochemistry. Biodistribution studies in control and EAE rats were performed using the TSPO radioligand [1?F]DPA-714 [N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide]. At 1 h after injection, almost fivefold higher levels of [1?F]DPA-714 were measured in spinal cords of EAE rats versus controls. The specific binding of [1?F]DPA-714 to TSPO in spinal cords was confirmed in competition studies, using unlabeled (R,S)-PK11195 [(R,S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide)] or DPA-714 in excess. MicroPET studies affirm that this differential radioactivity uptake in spinal cords of EAE versus control rats could be detected and quantified. Using [1?F]DPA-714, neuroinflammation in spinal cords of EAE-induced rats could be visualized by PET, offering a sensitive technique for monitoring neuroinflammatory lesions in the CNS and particularly in the spinal cord. In addition to current MRI protocols, this approach could provide molecular images of neuroinflammation for detection, monitoring, and research in MS.     

Combined 18F-fluorodeoxyglucose positron emission tomography and event-related potentials study of the cognitive impairment mechanisms in Parkinson’s disease

This study aimed to analyze positron emission tomography with 18F-fluorodeoxyglucose data and event-related potentials in the Go/NoGo paradigm in patients with Parkinson’s disease with and without cognitive impairment. In the group of cognitively impaired patients, glucose metabolism was decreased in the frontal, parietal, cingulate and posterior temporal cortex. Correlations were found between the cognitive scores and cerebral glucose metabolism in those areas. Event-related potentials analysis revealed a decrease in the amplitude of the late positive wave (P300 NoGo wave) in the group of cognitively impaired patients. The analysis revealed that decline in amplitude of P300 wave was accompanied by decreased glucose metabolism in several cortical areas associated with cognitive impairment in Parkinson’s disease. Correlations of glucose metabolism in these areas with event-related potentials amplitude in the NoGo condition confirm the important role of executive functions disorders in the pathogenesis of cognitive impairment in Parkinson’s disease.     

Volume,metabolites and neuroinflammation of the hippocampus in bipolar disorder – A combined magnetic resonance imaging and positron emission tomography study

BackgroundThe hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning.Materials and methodsTwenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [¹¹C]-(R)-PK11195 neuroinflammation positron emission tomography scan.ResultsIn contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA) + N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr) + phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA + NAAG concentration, between alcohol use and NAA + NAAG concentration, between microglial activation and the depression score and a negative relation between Cr + PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally.ConclusionCompared to HCs, the decreased NAA + NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.     

Effect of cerebral lymphatic block on cerebral morphology and cortical evoked potential in rats

BACKGROUND: It has been shown that although brain does not contain lining endothelial lymphatic vessel, it has lymphatic drain. Anterior lymphatic system of lymphatic vessel in brain tissue plays a key role in introducing brain interstitial fluid to lymphatic system; however, the significance of lymphatic drain and the effect on cerebral edema remains unclear. OBJECTIVE: To investigate the effect of cerebral lymphatic block on cerebral morphology and cortical evoked potential in rats. DESIGN: Randomized controlled animal study. SETTING: Institute of Cerebral Microcirculation of Taishan Medical College and Department of Neurology of Affiliated Hospital. MATERIALS: A total of 63 healthy adult male Wistar rats weighing 300-350 g were selected in this study. Forty-seven rats were used for the morphological observation induced by lymphatic drain and randomly divided into three groups: general observation group (n =12), light microscopic observation group (n =21) and electronic microscopic observation group (n =14). The rats in each group were divided into cerebral lymphatic block subgroup and sham-operation control subgroup. Sixteen rats were used for observing the effect of cerebral lymphatic block on cortical evoked potential, in which the animals were randomly divided into sham-operation group (n =6) and cerebral lymphatic block group (n =10). METHODS: The experiment was carried out in the Institute of Cerebral Microcirculation of Taishan Medical College from January to August 2003. Rats in cerebral lymphatic block group were anesthetized and separated bilateral superficial and deep cervical lymph nodes under sterile condition. Superior and inferior boarders of lymph nodes were ligated the inputting and outputting channels, respectively, and then lymph node was removed so as to establish cerebral lymphatic drain disorder models. Rats in sham-operation control group were not ligated the lymphatic vessel and removed lymph nodes, and other operations were as the same as those in cerebral lymphatic block group. Morphological changes of the brain and alterations of latency of cortical evoked potential were detected on the 1st, 2nd, 3rd, 5th, 7th, 10th and 15th days after operation under general, light microscope and electronic microscope observations. MAIN OUTCOME MEASURES: ① Cerebral morphological changes; ② latent changes of cortical evoked potential. RESULTS: A total of 63 rats were involved in the final analysis. ① Cerebral morphological changes: General observation showed that, for cerebral lymphatic block rats, the surface of brain was pale and full, and cerebral gyrus was wide and flattened sulci after cerebral lymphatic block; and cerebral tissue space prolongation, increased interstitial fluid, neuronal degeneration and necrosis, diffused phagocytes and satellitosis were observed under light microscope. Neuronal swell and necrosis, glial cell swell, apparent subcellular changes such as mitochondron were observed under electronic microscope. ② Latent changes of cortical evoked potential: As compared with sham-operation control group, latency of cortical evoked potential in cerebral lymphatic blockage group prolonged on the 5th day and 7th day after cerebral lymphatic block [(6.28±0.23), (6.97±0.35) ms; (6.23±0.22), (7.12±0.20) ms; P < 0.01]. CONCLUSION: ① Cerebral lymphatic block plays an important role in cerebral morphology, and may result in abnormality of sensitive impulse conduction and prolong latency of cortical evoked potential. ② Examination of cortical evoked potential is easy and convenient, so it is regarded as a key index for lymphatic disturbed cerebral injury.     

Regional brain kinetics of 6-fluoro-(β-11C)-L-dopa and (β-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography

Summary The regional brain kinetics of (-11C)-L-dopa and 6-fluoro-(-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 ± 0.0007 (S.D) and 0.0057 ± 0.0006 min1 for (-11C)-L-dopa and 6-fluoro-(-11C)-L-dopa, respectively. After pre-treatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 ± 0.0015 min-1) for (11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(-11C)L-dopa (0.0092 ± 0.0015 min–1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(-11C)-L-dopa significantly contributes to background radioactivity.     

The 5-HT(2A) receptor and serotonin transporter in Asperger's disorder: A PET study with [¹¹C]MDL 100907 and [¹¹C]DASB

Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [(11)C]MDL 100907 and [(11)C]DASB to characterize the 5-HT(2A) receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age=34.3 ± 11.1 years) and 17 healthy controls (age=33.0 ± 9.6 years) were scanned with [(11)C]MDL 100907. Of the 17 patients, eight (age=29.7 ± 7.0 years) were also scanned with [11C]DASB, as were eight healthy controls (age=28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP(ND). Neither regional [11C]MDL 100907 BP(ND) nor [11C]DASB BP(ND) was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT(2A) receptors and serotonin transporters in adult subjects with Asperger's disorder.     

Amyloid positron emission tomography with 18F-flutemetamol and structural magnetic resonance imaging in the classification of mild cognitive impairment and Alzheimer’s disease

ObjectiveTo evaluate the contributions of amyloid-positive (Am+) and medial temporal atrophy–positive (MTA+) scans to the diagnostic classification of prodromal and probable Alzheimer’s disease (AD).Methods¹⁸F-flutemetamol-labeled amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) were used to classify 10 young normal, 15 elderly normal, 20 amnestic mild cognitive impairment (aMCI), and 27 AD subjects. MTA+ status was determined using a cut point derived from a previous study, and Am+ status was determined using a conservative and liberal cut point.ResultsThe rates of MRI scans with positive results among young normal, elderly normal, aMCI, and AD subjects were 0%, 20%, 75%, and 82%, respectively. Using conservative cut points, the rates of Am+ scans for these same groups of subjects were 0%, 7%, 50%, and 93%, respectively, with the aMCI group showing the largest discrepancy between Am+ and MTA+ scans. Among aMCI cases, 80% of Am+ subjects were also MTA+, and 70% of amyloid-negative (Am−) subjects were MTA+. The combination of amyloid PET and MTA data was additive, with an overall correct classification rate for aMCI of 86%, when a liberal cut point (standard uptake value ratio = 1.4) was used for amyloid positivity.Interpretation¹⁸F-flutemetamol PET and structural MRI provided additive information in the diagnostic classification of aMCI subjects, suggesting an amyloid-independent neurodegenerative component among aMCI subjects in this sample.