Serotonin Synthesis Rate Measured in Living Dog Brain by Positron Emission Tomography

In vivo measurements by positron emission tomography of the brain serotonin synthesis rates in the normal dog, in the dog with increased plasma tryptophan concentration, and in the dog under different arterial oxygen tensions are described. The method described here permits repeated measurements in the same brain for the first time. An increase in the plasma tryptophan concentration from 16.6 to 191.5 and then to 381 microM resulted in close to a linear increase in the brain serotonin synthesis rate. When PaO2 was raised from 76 +/- 2 to 106 +/- 1 mm Hg, the rate of serotonin synthesis in the dog brain increased from 39 +/- 8 to 54 +/- 10 pmol g-1 min-1. The estimates of the Michaelis-Menten constants, Kappm and Vmax, for the transport of tryptophan through the blood-brain barrier are 303 +/- 54 microM and 63 +/- 10 nmol g-1 min-1, respectively.     

Neurophysiological Evidence of Compensatory Brain Mechanisms in Early-Stage Multiple Sclerosis

Multiple sclerosis (MS) is a chronic central nervous system disorder characterized by white matter inflammation, demyelination and neurodegeneration. Although cognitive dysfunction is a common manifestation, it may go unnoticed in recently-diagnosed patients. Prior studies suggest MS patients develop compensatory mechanisms potentially involving enhanced performance monitoring. Here we assessed the performance monitoring system in early-stage MS patients using the error-related negativity (ERN), an event-related brain potential (ERP) observed following behavioral errors. Twenty-seven early-stage MS patients and 31 controls were neuropsychologically assessed. Electroencephalography recordings were obtained while participants performed: a) a stop task and b) an auditory oddball task. Behavior and ERP measures were assessed. No differences in performance were found between groups in most neuropsychological tests or in behavior or ERP components in the auditory oddball task. However, the amplitude of the ERN associated with stop errors in the stop task was significantly higher in patients. ERN amplitude correlated positively with scores on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and negatively with the time since last relapse. Patients showed higher neuronal recruitment in tasks involving performance monitoring. Results suggest the development of compensatory brain mechanisms in early-stage MS and reflect the sensitivity of the ERN to detect these changes.     

Effect of Aspartame-Derived Phenylalanine on Neutral Amino Acid Uptake in Human Brain: A Positron Emission Tomography Study

The possible effects of elevation of the plasma phenylalanine level secondary to the ingestion of aspartame on brain amino acid uptake in human subjects have been investigated by means of positron emission tomography (PET). 1-[11C]Aminocyclohexanecarboxylate [( 11C]ACHC) is a poorly metabolized synthetic amino acid that crosses the blood-brain barrier by the same carrier that transports naturally occurring large neutral amino acids. Quantitative test-retest PET studies were performed on 15 individuals. Seven received two identical baseline scans, whereas eight received a baseline scan followed by a scan performed approximately 40-45 min following ingestion of an orange-flavored beverage containing 34 mg/kg of body weight of the low-calorie sweetener aspartame, a dose equivalent to the amount in 5 L of diet soft drink consumed all at once by the study subjects, weighing an average of 76 kg. The 40-45-min interval was selected to maximize the detection of possible decreases in ACHC uptake resulting from increased competition for the carrier, because the plasma phenylalanine level is known to peak at this time. We observed an 11.5% decrease in the amino acid transport rate constant K1 and a smaller decrease in the tissue distribution volume of ACHC (6%). Under conditions of normal dietary use, aspartame is thus unlikely to cause changes in brain amino acid uptake that are measurable by PET.     

Proteomic Approaches to Decipher Mechanisms Underlying Pathogenesis in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). The cause of MS is unknown, with no effective therapies available to halt the progressive neurological disability. Development of new and improvement of existing therapeutic strategies therefore require a better understanding of MS pathogenesis, especially during the progressive phase of the disease. This can be achieved through development of biomarkers that can help to identify disease pathophysiology and monitor disease progression. Proteomics is a powerful and promising tool to accelerate biomarker detection and contribute to novel therapeutics. In this review, an overview of how proteomic technology using CNS tissues and biofluids from MS patients has provided important clues to the pathogenesis of MS is provided. Current publications, pitfalls, as well as directions of future research involving proteomic approaches to understand the pathogenesis of MS are discussed.     

臂丛神经撕脱伤后慢性疼痛患者脑区葡萄糖代谢的研究

臂丛神经撕脱伤后慢性疼痛是一种临床上顽固性神经病理性疼痛.然而,对于其潜在的中枢机制还知之甚少.为了进一步探讨臂丛神经撕脱伤后慢性疼痛的相关脑区活动,利用18F-脱氧葡萄糖(FDG)正电子断层扫描(PET)技术观察臂丛神经撕脱后慢性疼痛患者的脑葡萄糖代谢.选择左侧臂丛神经撕脱伤后慢性疼痛行脊髓后根入髓区(DREZ)切开术后疼痛减轻>75%的患者,共5例,分别在术前和术后14天行PET扫描采集数据,同时行视觉模拟评分(VAS),汉密尔顿(Hamilton)抑郁和焦虑评分.用统计参数图(SPM2)软件分析数据.与术前疼痛状态下相比,术后葡萄糖代谢明显减低的脑区有双侧尾状核,眶额回(OFC)(BA11),对侧扣带下回(BA25)和同侧前额叶背外侧区域(DLPFC)(BA46/47).葡萄糖代谢明显增高的脑区有对侧丘脑,枕核和同侧项叶(BA7).研究结果提示,涉及情绪、注意和疼痛内在调节的脑区在臂丛神经撕脱伤后慢性疼痛的调制中发挥重要作用.     

Alcohol ADME in Primates Studied with Positron Emission Tomography

Background and Purpose

The sensitivity to the intoxicating effects of alcohol as well as its adverse medical consequences differ markedly among individuals, which reflects in part differences in alcohol''s absorption, distribution, metabolism, and elimination (ADME) properties. The ADME of alcohol in the body and its relationship with alcohol''s brain bioavailability, however, is not well understood.

Experimental Approach

The ADME of C-11 labeled alcohol, CH₃ ¹¹CH₂OH, 1 and C-11 and deuterium dual labeled alcohol, CH₃ ¹¹CD₂OH, 2 in baboons was compared based on the principle that C–D bond is stronger than C–H bond, thus the reaction is slower if C–D bond breaking occurs in a rate-determining metabolic step. The following ADME parameters in peripheral organs and brain were derived from time activity curve (TAC) of positron emission tomography (PET) scans: peak uptake (C_max); peak uptake time (T_max), half-life of peak uptake (T_1/2), the area under the curve (AUC_60min), and the residue uptake (C_60min).

Key Results

For 1 the highest uptake occurred in the kidney whereas for 2 it occurred in the liver. A deuterium isotope effect was observed in the kidneys in both animals studied and in the liver of one animal but not the other. The highest uptake for 1 and 2 in the brain was in striatum and cerebellum but 2 had higher uptake than 1 in all brain regions most evidently in thalamus and cingulate. Alcohol''s brain uptake was significantly higher when given intravenously than when given orally and also when the animal was pretreated with a pharmacological dose of alcohol.

Conclusion and Implications

The study shows that alcohol metabolism in peripheral organs had a large effect on alcohol''s brain bioavailability. This study sets the stage for clinical investigation on how genetics, gender and alcohol abuse affect alcohol''s ADME and its relationship to intoxication and medical consequences.     

Functional Plasticity after Unilateral Vestibular Midbrain Infarction in Human Positron Emission Tomography

The aim of the study was to uncover mechanisms of central compensation of vestibular function at brainstem, cerebellar, and cortical levels in patients with acute unilateral midbrain infarctions presenting with an acute vestibular tone imbalance. Eight out of 17 patients with unilateral midbrain infarctions were selected on the basis of signs of a vestibular tone imbalance, e.g., graviceptive (tilts of perceived verticality) and oculomotor dysfunction (skew deviation, ocular torsion) in F18-fluordeoxyglucose (FDG)-PET at two time points: A) in the acute stage, and B) after recovery 6 months later. Lesion-behavior mapping analyses with MRI verified the exact structural lesion sites. Group subtraction analyses and comparisons with healthy controls were performed with Statistic Parametric Mapping for the PET data. A comparison of PET A of acute-stage patients with that of healthy controls showed increases in glucose metabolism in the cerebellum, motion-sensitive visual cortex areas, and inferior temporal lobe, but none in vestibular cortex areas. At the supratentorial level bilateral signal decreases dominated in the thalamus, frontal eye fields, and anterior cingulum. These decreases persisted after clinical recovery in contrast to the increases. The transient activations can be attributed to ocular motor and postural recovery (cerebellum) and sensory substitution of vestibular function for motion perception (visual cortex). The persisting deactivation in the thalamic nuclei and frontal eye fields allows alternative functional interpretations of the thalamic nuclei: either a disconnection of ascending sensory input occurs or there is a functional mismatch between expected and actual vestibular activity. Our data support the view that both thalami operate separately for each hemisphere but receive vestibular input from ipsilateral and contralateral midbrain integration centers. Normally they have gatekeeper functions for multisensory input to the cortex and automatic motor output to subserve balance and locomotion, as well as sensorimotor integration.     

Evidence of Nitrosative Damage in the Brain White Matter of Patients with Multiple Sclerosis

Nitric oxide (NO) has been implicated in the pathophysiology of both experimental autoimmune encephalomyelitis and multiple sclerosis (MS). NO-mediated protein damage in MS appears to be confined to large plaques where 3-nitrotyrosine has been detected. To determine whether nitrosative damage takes place beyond visible MS plaques, the occurrence of various NO-triggered protein modifications in normal-appearing white matter (NAWM) of eight MS brains was assessed and compared to that in white matter (WM) of four control brains. As determined by amino acid analysis and western blotting, no evidence of tyrosine nitration was found in the MS samples studied, suggesting that they did not contain appreciable amounts of plaque-derived material. The amino acid composition of total myelin proteins and proteolipid protein (PLP) was also unaltered in the diseased tissue, as was the fatty acid composition of PLP. In addition, we detected no changes in the number of protein free thiols suggesting that oxidation do not occur to any appreciable extent. However, the levels of nitrite in MS-NAWM were higher than those in control WM, while in the MS-gray matter (GM) the concentration of this ion was unaltered. Furthermore, five of the MS samples analyzed, and the same as those with high levels of glial fibrilary acidic protein, showed increased amounts of protein nitrosothiols as determined by the biotin switch method. S-nitrosation of GM proteins was again normal. There was no indication of N-nitrosation of tryptophan and N-terminal amino groups in both control and MS tissue. Overall, the data suggests that WM, but not GM, from MS brains is subjected to considerable nitrosative stress. This is the first report to present direct evidence of increased protein S-nitrosation and nitrite content in the brain parenchyma of MS patients.     

Relation between Dopamine Synthesis Capacity and Cell-Level Structure in Human Striatum: A Multi-Modal Study with Positron Emission Tomography and Diffusion Tensor Imaging

Positron emission tomography (PET) study has shown that dopamine synthesis capacity varied among healthy individuals. This interindividual difference might be due to a difference in the cell-level structure of presynaptic dopaminergic neurons, i.e., cellular density and/or number. In this study, the relations between the dopamine synthesis capacity measured by PET and the parameter estimates in diffusion tensor imaging (DTI) in striatal subregions were investigated in healthy human subjects. DTI and PET studies with carbon-11 labeled L-DOPA were performed in ten healthy subjects. Age-related changes in the above parameters were also considered. Fractional anisotropy showed a significant positive correlation with age in the posterior caudate. There was significant negative correlation between dopamine synthesis capacity and mean diffusivity in the posterior caudate and putamen. Assuming that mean diffusivity reflects the density of wide-spreading axonal terminals in the striatum, the result suggests that dopamine synthesis may be related to the density of dopaminergic neuronal fibers. It is evident that PET/DTI combined measurements can contribute to investigations of the pathophysiology of neuropsychiatric diseases involving malfunction of dopaminergic neurons.     

Prognostic Value of SUVmax Measured by Pretreatment Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Patients with Ewing Sarcoma

AimThe aim of this retrospective study was to determine whether glucose metabolism assessed by using Fluorine-18 (F-18) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) provides prognostic information independent of established prognostic factors in patients with Ewing sarcoma.MethodsWe retrospectively reviewed the medical records of 34 patients (men, 19; women, 15; mean age, 14.5 ± 9.7 years) with pathologically proven Ewing sarcoma. They had undergone F-18 FDG PET/CT as part of a pretreatment workup between September 2006 and April 2012. In this analysis, patients were classified by age, sex, initial location, size, and maximum standardized uptake value (SUVmax). The relationship between FDG uptake and survival was analyzed using the Kaplan-Meier method with the log-rank test and Cox’s proportional hazards regression model.ResultsThe median survival time for all 34 subjects was 999 days and the median SUV by using PET/CT was 5.8 (range, 2–18.1). Patients with a SUVmax ≤ 5.8 survived significantly longer than those with a SUVmax > 5.8 (median survival time, 1265 vs. 656 days; p = 0.002). Survival was also found to be significantly related to age (p = 0.024), size (p = 0.03), and initial tumor location (p = 0.036). Multivariate analysis revealed that a higher SUVmax (p = 0.003; confidence interval [CI], 3.63–508.26; hazard ratio [HR], 42.98), older age (p = 0.023; CI, 1.34–54.80; HR, 8.59), and higher stage (p = 0.03; CI, 1.21–43.95; HR, 7.3) were associated with worse overall survival.ConclusionsSUVmax measured by pretreatment F-18-FDG PET/CT can predict overall survival in patients with Ewing sarcoma.     

18F-Fluorodeoxyglucose Positron Emission Tomography in Elderly Patients with an Elevated Erythrocyte Sedimentation Rate of Unknown Origin

Patients with an elevated erythrocyte sedimentation rate (ESR) and non-specific symptoms often pose a diagnostic dilemma. PET/CT visualises infection, inflammation and malignancy, all of which may cause elevated ESR. The objective of this study was to determine the contribution of 18F-fluorodeoxglucose positron emission tomography (PET/CT) in the diagnostic work-up of referred patients with an elevated ESR, in whom initial routine evaluation did not reveal a diagnosis. We conducted a combined retrospective (A) and prospective (B) study in elderly (>50 years) patients with a significantly elevated ESR of≥50 mm/h and non-specific complaints. In study A, 30 patients were included. Malignancy (8 patients), auto-inflammatory disease (8 patients, including 5 with large-vessel vasculitis) and infection (3 patients) were suggested by PET/CT. Two scans showed non-specific abnormalities and 9 scans were normal. Of the 21 abnormal PET/CT results, 12 diagnoses were independently confirmed and two alternative diagnosis were made. Two diagnoses were established in patients with a normal scan. In study B, 58 patients in whom a prior protocolised work-up was non-diagnostic, were included. Of these, 25 PET/CT-scans showed suspected auto-inflammatory disease, particularly large-vessel vasculitis (14 cases). Infection and malignancy was suspected in 5 and 3 cases, respectively. Seven scans demonstrated non-specific abnormalities, 20 were normal. Of the 40 abnormal PET/CT results, 22 diagnoses were confirmed, 3 alternative diagnoses were established. Only one diagnosis was established in the 20 patients with a normal scan. In both studies, the final diagnosis was based on histology, clinical follow-up, response to therapy or additional imaging. In conclusion, PET/CT may be of potential value in the diagnostic work-up of patients with elevated ESR if routine evaluation reveals no diagnosis. In particular, large-vessel vasculitis appears to be a common finding. A normal PET/CT scan in these patients suggests that it is safe to follow a wait-and-see policy.     

Poor Sleep in Patients with Multiple Sclerosis

Background

Poor sleep is a frequent symptom in patients with multiple sclerosis (MS). Sleep may be influenced by MS-related symptoms and adverse effects from immunotherapy and symptomatic medications. We aimed to study the prevalence of poor sleep and the influence of socio-demographic and clinical factors on sleep quality in MS- patients.

Methods

A total of 90 MS patients and 108 sex-and age- matched controls were included in a questionnaire survey. Sleep complaints were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a global PSQI score was used to separate good sleepers (≤5) from poor sleepers (>5). Excessive daytime sleepiness, the use of immunotherapy and antidepressant drugs, symptoms of pain, depression, fatigue and MS-specific health related quality of life were registered. Results were compared between patients and controls and between good and poor sleepers among MS patients.

Results

MS patients reported a higher mean global PSQI score than controls (8.6 vs. 6.3, p = 0.001), and 67.1% of the MS patients compared to 43.9% of the controls (p = 0.002) were poor sleepers. Pain (p = 0.02), fatigue (p = 0.001), depression (p = 0.01) and female gender (p = 0.04) were associated with sleep disturbance. Multivariate analyses showed that female gender (p = 0.02), use of immunotherapy (p = 005) and a high psychological burden of MS (p = 0.001) were associated with poor sleep among MS patients.

Conclusions

Poor sleep is common in patients with MS. Early identification and treatment of modifiable risk factors may improve sleep and quality of life in MS.     

Mechanisms Underlying the Process of Demyelination in Multiple Sclerosis

The author generalizes and analyzes the published data and her own findings related to the cellular and molecular mechanisms underlying a demyelinating disease, multiple sclerosis. The mechanisms of the immunopathogenic process in multiple sclerosis, the involvement of microglia and astrocytes in destruction of the myelin sheaths, and injury of oligodendrocytes are discussed. Experimental models used for examination of the processes of demyelination of the nerve tissue in vitro (tissue cultures) and in vivo (experimental allergic encephalomyelitis) are also described.     

[18F]-Fluorodeoxyglucose Positron Emission Tomography Can Contribute to Discriminate Patients with Poor Prognosis in Hormone Receptor-Positive Breast Cancer

Background

Patients with hormone receptor-positive breast cancer typically show favorable survival. However, identifying individuals at high risk of recurrence among these patients is a crucial issue. We tested the hypothesis that [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans can help predict prognosis in patients with hormone receptor-positive breast cancer.

Methods

Between April 2004 and December 2008, 305 patients with hormone receptor-positive breast cancer who underwent FGD-PET were enrolled. Patients with luminal B subtype were identified by positivity for human epidermal growth factor receptor-2 (HER2) or high Ki67 (≥14%) according to criteria recently recommended by the St. Gallen panelists. The cut-off value of SUV_max was defined using the time-dependent receiver operator characteristic curve for recurrence-free survival (RFS).

Results

At a median follow up of 6.23 years, continuous SUV_max was a significant prognostic factor with a hazard ratio (HR) of 1.21 (p = 0.021). The cut-off value of SUV_max was defined as 4. Patients with luminal B subtype (n = 82) or high SUV_max (n = 107) showed a reduced RFS (p = 0.031 and 0.002, respectively). In multivariate analysis for RFS, SUV_max carried independent prognostic significance (p = 0.012) whereas classification with immunohistochemical markers did not (p = 0.274). The Harell c-index was 0.729. High SUV_max was significantly associated with larger tumor size, positive nodes, HER2 positivity, high Ki67 (≥14%), high tumor grade, and luminal B subtype.

Conclusions

Among patients with hormone receptor-positive breast cancer, FDG-PET can help discriminate patients at high risk of tumor relapse.     

Relevance of Brain Lesion Location to Cognition in Relapsing Multiple Sclerosis

Objective

To assess the relationship between cognition and brain white matter (WM) lesion distribution and frequency in patients with relapsing-remitting multiple sclerosis (RR MS).

Methods

MRI-based T2 lesion probability map (LPM) was used to assess the relevance of brain lesion location for cognitive impairment in a group of 142 consecutive patients with RRMS. Significance of voxelwise analyses was p<0.05, cluster-corrected for multiple comparisons. The Rao Brief Repeatable Battery was administered at the time of brain MRI to categorize the MS population into cognitively preserved (CP) and cognitively impaired (CI).

Results

Out of 142 RRMS, 106 were classified as CP and 36 as CI. Although the CI group had greater WM lesion volume than the CP group (p = 0.001), T2 lesions tended to be less widespread across the WM. The peak of lesion frequency was almost twice higher in CI (61% in the forceps major) than in CP patients (37% in the posterior corona radiata). The voxelwise analysis confirmed that lesion frequency was higher in CI than in CP patients with significant bilateral clusters in the forceps major and in the splenium of the corpus callosum (p<0.05, corrected). Low scores of the Symbol Digit Modalities Test correlated with higher lesion frequency in these WM regions.

Conclusions

Overall these results suggest that in MS patients, areas relevant for cognition lie mostly in the commissural fiber tracts. This supports the notion of a functional (multiple) disconnection between grey matter structures, secondary to damage located in specific WM areas, as one of the most important mechanisms leading to cognitive impairment in MS.     

In Vivo Imaging of Vesicular Monoamine Transporters in Human Brain Using [11C]Tetrabenazine and Positron Emission Tomography

Abstract: The pharmacokinetics of [¹¹CJtetrabenazine, a high-affinity radioligand for the monoamine vesicular transporter, were determined in living human brain using in vivo imaging by positron emission tomography (PET). The radiotracer showed high brain uptake and rapid washout from all brain regions with relatively slower clearance from regions of highest concentrations of monoamine vesicular transporters (striatum), resulting in clear differential visualization of these structures at short intervals after injection (10–20 min). As the first human PET imaging study of a vesicular neurotransmitter transporter, these experiments demonstrate that external imaging of vesicular transporters forms a new and valuable approach to the in vivo quantification of monoaminergic neurons, with potential application to the in vivo study of neurodegenerative disorders such as Parkinson's disease.     

Positron Emission Tomography and Magnetic Resonance Imaging of the Brain in Fabry Disease: A Nationwide,Long-Time,Prospective Follow-Up

Background

Fabry disease is a rare metabolic glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme α-galactosidase A—leading to cellular accumulation of globotriasylceramide in different organs, vessels, tissues, and nerves. The disease is associated with an increased risk of cerebrovascular disease at a young age in addition to heart and kidney failure.

Objective

The objective of this study was to assess brain function and structure in the Danish cohort of patients with Fabry disease in a prospective way using 18-fluoro-deoxyglucose (F-18 FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI).

Patients

Forty patients with Fabry disease (14 males, 26 females, age at inclusion: 10–66 years, median: 39 years) underwent a brain F-18-FDG-PET-scan at inclusion, and 31 patients were followed with FDG-PET biannually for up to seven years. All patients (except one) had a brain MRI-scan at inclusion, and 34 patients were followed with MRI biannually for up to nine years.

Image Analysis

The FDG-PET-images were inspected visually and analysed using a quantitative 3-dimensional stereotactic surface projection analysis (Neurostat). MRI images were also inspected visually and severity of white matter lesions (WMLs) was graded using a visual rating scale.

Results

In 28 patients brain-FDG-PET was normal; in 23 of these 28 patients brain MRI was normal—of the remaining five patients in this group, four patients had WMLs and one patient never had an MRI-scan. In 10 patients hypometabolic areas were observed on brain-FDG-PET; all of these patients had cerebral infarcts/hemorrhages visualized on MRI corresponding to the main hypometabolic areas. In two patients brain-FDG-PET was ambiguous, while MRI was normal in one and abnormal in the other.

Conclusion

Our data indicated that, in patients with Fabry disease, MRI is the preferable clinical modality—if applicable—when monitoring cerebral status, as no additional major brain-pathology was detected with FDG-PET.