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18F-fluoro-L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors
Because of the high glucose metabolism in normal brain tissue 18F-FDG is not the ideal tracer for the detection of gliomas. Methyl-11C-L-methionine (11C-MET) is better suited for imaging the extent of gliomas, because it is transported specifically into tumors but only insignificantly into normal brain. 3′-Deoxy-3′- 18F-fluorothymidine (18F-FLT) has been introduced as a proliferation marker in a variety of neoplasias and has promising potential for the detection of brain tumors, because its uptake in normal brain is low. Additionally, the longer half-life might permit differentiation between transport and intracellular phosphorylation. Methods: PET of 18F-FLT and 11C-MET was performed on 23 patients (age range, 20-70 y) with historically verified gliomas of different grades. On all patients, conventional MRI was performed, and 16 patients additionally underwent contrast-enhanced imaging. Images were coregistered, and the volumes of abnormality were defined for PET and MRI. Uptake ratios and standardized uptake values (SUVs) of various tumors and regions were assessed by region-of-interest analysis. Kinetic modeling was performed on 14 patients for regional time-activity curves of 18F-FLT from tumorous and normal brain tissue. Results: Sensitivity for the detection of tumors was lower for 18F-FLT than for 11C-MET (78.3% vs. 91.3%), especially for low-grade astrocytomas. Tumor volumes detected by 18F-FLT and 11C-MET were larger than tumor regions displaying gadolinium enhancement (P < 0.01). Uptake ratios of 18F-FLT were higher than uptake ratios of 11C-MET (P < 0.01). Uptake ratios of 18F-FLT were higher in glioblastomas than in astrocytomas (P < 0.01). Absolute radiotracer uptake of 18F-FLT was low and significantly lower than that of 11C-MET (SUV, 1.3 ± 0.7 vs. 3.1 ± 1.0; P < 0.01). Some tumor regions were detected only by either 18F-FLT (7 patients) or 11C-MET (13 patients). Kinetic modeling revealed that 18F-FLT uptake in tumor tissue seems to be predominantly due to elevated transport and net influx. However, a moderate correlation was found between uptake ratio and phosphorylation rate k3 (r = 0.65 and P = 0.01 for grade II-IV gliomas; r = 0.76 and P < 0.01 for grade III-IV tumors). Conclusion: 18F-FLT is a promising tracer for the detection and characterization of primary central nervous system tumors and might help to differentiate between low- and high-grade gliomas. 18F-FLT uptake is mainly due to increased transport, but irreversible incorporation by phosphorylation might also contribute. In some tumors and tumor areas, 18F-FLT uptake is not related to 11C-MET uptake. In view of the high sensitivity and specificity of 11C-MET PET for imaging of gliomas, it cannot be excluded that 18F-FLT PET was false positive in these areas. However, the discrepancies observed for the various imaging modalities (18F-FLT and 11C-MET PET as well as gadolinium-enhanced MRI) yield complementary information on the activity and the extent of gliomas and might improve early evaluation of treatment effects, especially in patients with high-grade gliomas. Further studies are needed, including coregistered histology and kinetic analysis in patients undergoing chemotherapy.
Dementia in Parkinson disease: Functional imaging of cholinergic and dopaminergic pathways
Objective: To assess neurochemical deficits in patients with Parkinson disease (PD) associated dementia (PDD) in vivo. Methods: The authors performed combined PET with N-[11C]-methyl-4-piperidyl acetate (MP4A) and 18F-fluorodopa (FDOPA) for evaluation of cholinergic and dopaminergic transmitter changes in 17 non-demented patients with PD and 10 patients with PDD. Data were compared to 31 age-matched controls by a combined region-of-interest and voxel-based Statistical Parametric Mapping analysis. Results: The striatal FDOPA uptake was significantly decreased in PD and PDD without differences between the groups. The global cortical MP4A binding was severely reduced in PDD (29.7%, p < 0.001 vs controls) and moderately decreased in PD (10.7%, p < 0.01 vs controls). The PDD group had lower parietal MP4A uptake rates than did patients with PD. Frontal and temporo-parietal cortices showed a significant covariance of striatal FDOPA reduction and decreased MP4A binding in patients with PDD. Conclusions: While non-demented patients with Parkinson disease had a moderate cholinergic dysfunction, subjects with Parkinson disease associated dementia (PDD) presented with a severe cholinergic deficit in various cortical regions. The finding of a closely associated striatal FDOPA and cortical MP4A binding reduction suggests a common disease process leading to a complex transmitter deficiency syndrome in PDD. Copyright © 2005 by AAN Enterprises, Inc.
Metabolic rates in small brain nuclei determined by high-resolution PET
Identification of small nuclei in the brain by PET has been limited by the spatial resolution of conventional scanners. The new detector technology and advanced signal analysis of a high-resolution research tomograph (HRRT) has improved 3-dimensional spatial resolution to 2.2 mm at sufficient efficiency and permitted the quantification of tracer concentrations in small volumes. Methods: In 9 healthy volunteers, cerebral glucose metabolism was investigated after intravenous injection of 370 MBq of 18F-FDG, and regional cerebral metabolic rates for glucose (rCMRGlc) were determined in various structures of the brain identified on coregistered MR images using stereotactic and topographic anatomic information. Results: rCMRGlc values (in μmol/100 g/min) were higher in the cerebral cortex (33.5 ± 2.98), the basal ganglia (32.6 ± 3.04 in the nucleus caudatus and 40.2 ± 3.50 in the putamen), the thalamus (36.6 ± 4.72), and the cerebellum (29.8 ± 2.20) and were lower in the cerebral white matter (12.3 ± 1.45) than those reported previously with conventional scanners. This resulted in an increased ratio of cortical values to white-matter values. Various nuclei in the basal frontal lobe (21.4 ± 3.19 in the basal forebrain and 32.3 ± 2.39 in the nucleus accumbens), the temporal lobe (22.2 ± 1.74 in the corpus amygdalae), the hippocampus (25.7 ± 2.11), the diencephalon (23.1 ± 3.33 in the corpus geniculatum laterale, 20.2 ± 2.87 in the corpus geniculatum mediale, and 25.2 ± 3.29 in the nucleus subthalamicus), and the brain stem (24.4 ± 2.47 in the colliculus superior, 31.4 ± 3.63 in the colliculus inferior, 31.0 ± 3.10 in the nucleus ruber, and 22.8 ± 2.35 in the substantia nigra) could be identified, and the metabolic rate was assessed in these structures. The effect of improved spatial resolution on quantified metabolic rates could directly be demonstrated in a few cases investigated on scanners of different generations. Conclusion: The improved spatial resolution of the HRRT decreased partial-volume effects in the quantification of metabolic rates in the brain and increased the accuracy of rCMRGlc values in large structures. For the first time, this scanner has permitted the determination of metabolic rates in small nuclei that are involved in various neurodegenerative disorders.
Delineation of brain tumor extent with [11C]L-methionine positron emission tomography: Local comparison with stereotactic histopathology
Purpose: Methyl-[11C]L-methionine ([11C]MET) positron emission tomography (PET) in brain tumors reflects amino acid transport and has been shown to be more sensitive than magnetic resonance imaging in stereotactic biopsy planning. It remains unclear whether the increased [11C]MET uptake is limited to solid tumor tissue or even detects infiltrating tumor parts. Experimental Design: In 30 patients, a primary or recurrent brain tumor was suspected on magnetic resonance imaging. Patients were investigated with [11C]MET-PET before stereotactic biopsy. The biopsy trajectories were plotted into the [11C]MET-PET images with a newly designed C-based software program. The exact local [11C]MET uptake was determined within rectangular regions of interest of 4 mm in width and length aligned with the biopsy specimen. Individual histologic specimens were rated for the presence of solid tumor tissue, infiltration area, and nontumorous tissue changes. Results: Receiver operating characteristics analysis demonstrated a sensitivity of 87% and specificity of 89% for the detection of tumor tissue at a threshold of 1.3-fold [11C]MET uptake relative to normal brain tissue. At this threshold, only 13 of 100 tumor positive specimen were false negative mainly in grade 2 astrocytoma. In grade 2 astrocytoma, mean [11C]MET uptake in the infiltration area was significantly higher than in solid tumor tissue (P < 0.003). Conclusions: [11C]MET-PET detects solid parts of brain tumors, as well as the infiltration area at high sensitivity and specificity. High [11C]MET uptake in infiltrating tumor of astrocytoma WHO grade 2 reflects high activity in this tumor compartment. Molecular imaging, with [11C]MET, will guide improved management of patients with brain tumors.
Fast and robust registration of PET and MR images of human brain
In recent years, mutual information has proved to be an excellent criterion for registration of intra-individual images from different modalities. Multi-resolution coarse-to-fine optimization was proposed for speeding-up of the registration process. The aim of our work was to further improve registration speed without compromising robustness or accuracy. We present and evaluate two procedures for co-registration of positron emission tomography (PET) and magnetic resonance (MR) images of human brain that combine a multi-resolution approach with an automatic segmentation of input image volumes into areas of interest and background. We show that an acceleration factor of 10 can be achieved for clinical data and that a suitable preprocessing can improve robustness of registration. Emphasis was laid on creation of an automatic registration system that could be used routinely in a clinical environment. For this purpose, an easy-to-use graphical user interface has been developed. It allows physicians with no special knowledge of the registration algorithm to perform a fast and reliable alignment of images. Registration progress is presented on the fly on a fusion of images and enables visual checking during a registration. © 2004 Elsevier Inc. All rights reserved.
The nucleus accumbens: A target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders
We considered clinical observations in patients with obsessive-compulsive- and anxiety-disorders, who underwent bilateral anterior capsulotomy, as well as anatomical and pathophysiological findings. Based on these considerations, we choose the shell region of the right nucleus accumbens as target for deep brain stimulation (DBS) in a pilot-series of four patients with severe obsessive-compulsive- and anxiety-disorders. Significant reduction in severity of symptoms has been achieved in three of four patients treated. Clinical results as well as a 15-O-H2O-PET study, perfomed in one patient during stimulation, speak in favour of the following hypothesis. As a central relay-structure between amygdala, basal ganglia, mesolimbic dopaminergic areas, mediodorsal thalamus and prefrontal cortex, the accumbens nucleus seems to play a modulatory role in information flow from the amygdaloid complex to the latter areas. If disturbed, imbalanced information flow from the amygdaloid complex could yield obsessive-compulsive- and anxiety-disorders, which can be counteracted by blocking the information flow within the shell region of the accumbens nucleus by deep brain stimulation. © 2003 Published by Elsevier B.V.
Delayed rat facial nerve repair leads to accelerated and enhanced muscle reinnervation with reduced collateral axonal sprouting during a definite denervation period using a cross-anastomosis paradigm
To establish the influence of prolonged denervation on the recovery of a motor nerve, the rat facial nerve was transected and denervated for 0 to 224 days. Then, the freshly transected hypoglossal nerve was sutured to the predegenerated facial nerve (hypoglossal-facial nerve anastomosis, HFA). Using this nerve cross-anastomosis paradigm we analyzed the nerve regeneration and muscle reinnervation 7 to 112 days post-suture operation (DPSO). After HRP injection into the whiskerpad 931 ± 27 hypoglossal neurons were labeled at 112 DPSO after immediate HFA. Following 14 to 112 days denervation the number of labeled neurons increased to 138% (14 days delay), 154% (56 days), and 145% (112 days). In contrast, the reinnervation was poorer after 7 days denervation with the number of neurons increasing to 84%, and after long-term denervation of 224 days the number of neurons increased to 81%. The increase in amplitude of evoked electromyography wave after nerve suture correlated with the number of labeled neurons. After immediate HFA each regenerated motoneuron established on average 5.1 myelinated sprouts at 112 DPSO. The number of sprouts remained constant after delayed suture of 14 to 112 days, whereas the slower reinnervation after 7 or 224 days delay was accompanied by a massive sprouting of 9.1 or 8.1, respectively, sprouts per neuron. The muscles showed recovery after any denervation time. The muscle cross-sectional area continuously decreased with longer denervation time. This decrease was only significant after 224 days denervation (67% of the normal value). We conclude that motor nerve reconstruction achieves better functional results after a definite period of denervation when using a nerve cross-anastomosis paradigm. (C) 2000 Academic Press.
Cholinergic degeneration in prodromal and early Parkinson's: a link to present and future disease states.
The neuropathological process in Parkinson's disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain which play crucial roles in the clinical expression and progression of these disorders. Here, we investigate the role of the macrostructural integrity of the nucleus basalis of Meynert (NbM), the main source of cholinergic input to the cerebral cortex, in cognitive function, clinical manifestation, and disease progression in non-demented subjects with PD and individuals with isolated REM sleep behaviour disorder (iRBD). Using structural MRI data from 393 early PD patients, 128 iRBD patients, and 186 controls from two longitudinal cohorts, we found significantly lower NbM grey matter volume in both PD (β=-12.56, p=0.003) and iRBD (β=-16.41, p=0.004) compared to controls. In PD, higher NbM volume was associated with better higher-order cognitive function (β=0.10, p=0.045), decreased non-motor (β=-0.66, p=0.026) and motor (β=-1.44, p=0.023) symptom burden, and lower risk of future conversion to dementia (Hazard ratio (HR)<0.400, p<0.004). Higher NbM volume in iRBD was associated with decreased future risk of phenoconversion to PD or dementia with Lewy bodies (DLB) (HR<0.490, p<0.016). However, despite similar NbM volume deficits to those seen in PD, associations between NbM structural deficits and current disease burden or clinical state were less pronounced in iRBD. These findings identify NbM volume as a potential biomarker with dual utility: predicting cognitive decline and disease progression in early PD, while also serving as an early indicator of phenoconversion risk in prodromal disease. The presence of structural deficits before clear clinical correlates in iRBD suggests complex compensatory mechanisms may initially mask cholinergic dysfunction, with subsequent failure of these mechanisms potentially contributing to clinical conversion.
Dorsal raphe nucleus controls motivation-state transitions in monkeys.
The dorsal raphe nucleus (DRN) is an important source of serotonin in the brain, but fundamental aspects of its function remain elusive. Here, we present a combination of minimally invasive recording and disruption studies to show that DRN brings about changes in motivation states. We use recently developed methods for identifying temporal patterns in behavior to show that monkeys change their motivation depending on the availability of rewards in the environment. Distinctive patterns of DRN activity occur when monkeys transition between a high-motivation state occupied when rewards are abundant, to a low-motivation state engendered by reward scarcity. Disrupting DRN diminishes sensitivity to the reward environment and perturbs transitions in motivational states.
A Survey of Preferences for Sensing Technologies in People with Severe Mental Illness Admitted to an Acute Psychiatric Unit.
PURPOSE: This study presents the views of patients admitted to an adult acute mental health unit due to an acute episode of severe mental illness, mainly of a psychotic nature, regarding sensing technology. METHODS: One hundred and twenty five adult inpatients were approached; 31 patients declined to participate whilst eleven patients were missed due to having been discharged from hospital or transferred to a different unit. Eighty three patients consented to participate and were administered a survey, previously validated in people with arthritis and other physical health conditions, about their preferences regarding sensing technology. The participants' clinical presentation was characterised using standard clinical instruments. RESULTS: Ninety percent of participants were on antipsychotic medication and 78% were detained in hospital under the Mental Health Act 1983 of England and Wales. 67.9% exhibited elevated levels of ideas of reference and 61.7% presented a clinical level of persecutory delusions. Patients' views about wearable digital technology were broadly positive and similar to those previously provided by people with arthritis and physical health conditions, with some specific differences. For example, they agreed to wear a device that is visible to others but less so to wearing one that is concealed in their clothing or implanted or for 24 h monitoring with the data being sent away, analysed or stored. CONCLUSION: This study shows that those who are in the middle of an acute and severe episode of mental ill health are open to using sensing technology, with some specific requirements that would increase the uptake within this patient population. This research shows that this currently underserved patient population has a positive view with regards to sensing technology for healthcare purposes. These findings can inform the design of new wearable systems, which can address the unmet needs in this clinical domain.
A cognitive map for value-guided choice in the ventromedial prefrontal cortex.
The prefrontal cortex (PFC) is crucial for economic decision-making. However, how PFC value representations facilitate flexible decisions remains unknown. We reframe economic decision-making as a navigation process through a cognitive map of choice values. We found rhesus macaques represented choices as navigation trajectories in a value space using a grid-like code. This occurred in ventromedial PFC (vmPFC) local field potential theta frequency across two datasets. vmPFC neurons deployed the same grid-like code and encoded chosen value. However, both signals depended on theta phase: occurring on theta troughs but on separate theta cycles. Finally, we found sharp-wave ripples-a key signature of planning and flexible behavior-in vmPFC. Thus, vmPFC utilizes cognitive map-based computations to organize and compare values, suggesting an alternative architecture for economic choice in PFC.
Neural mechanisms of credit assignment for delayed outcomes during contingent learning.
Adaptive behavior in complex environments critically relies on the ability to appropriately link specific choices or actions to their outcomes. However, the neural mechanisms that support the ability to credit only those past choices believed to have caused the observed outcomes remain unclear. Here, we leverage multivariate pattern analyses of functional magnetic resonance imaging (fMRI) data and an adaptive learning task to shed light on the underlying neural mechanisms of such specific credit assignment. We find that the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) code for the causal choice identity when credit needs to be assigned for choices that are separated from outcomes by a long delay, even when this delayed transition is punctuated by interim decisions. Further, we show when interim decisions must be made, learning is additionally supported by lateral frontopolar cortex (lFPC). Our results indicate that lFPC holds previous causal choices in a 'pending' state until a relevant outcome is observed, and the fidelity of these representations predicts the fidelity of subsequent causal choice representations in lOFC and HC during credit assignment. Together, these results highlight the importance of the timely reinstatement of specific causes in lOFC and HC in learning choice-outcome relationships when delays and choices intervene, a critical component of real-world learning and decision making.
Constructing future behavior in the hippocampal formation through composition and replay.
The hippocampus is critical for memory, imagination and constructive reasoning. Recent models have suggested that its neuronal responses can be well explained by state spaces that model the transitions between experiences. Here we use simulations and hippocampal recordings to reconcile these views. We show that if state spaces are constructed compositionally from existing building blocks, or primitives, hippocampal responses can be interpreted as compositional memories, binding these primitives together. Critically, this enables agents to behave optimally in new environments with no new learning, inferring behavior directly from the composition. We predict a role for hippocampal replay in building and consolidating these compositional memories. We test these predictions in two datasets by showing that replay events from newly discovered landmarks induce and strengthen new remote firing fields. When the landmark is moved, replay builds a new firing field at the same vector to the new location. Together, these findings provide a framework for reasoning about compositional memories and demonstrate that such memories are formed in hippocampal replay.
A tale of two algorithms: Structured slots explain prefrontal sequence memory and are unified with hippocampal cognitive maps.
Remembering events is crucial to intelligent behavior. Flexible memory retrieval requires a cognitive map and is supported by two key brain systems: hippocampal episodic memory (EM) and prefrontal working memory (WM). Although an understanding of EM is emerging, little is understood of WM beyond simple memory retrieval. We develop a mathematical theory relating the algorithms and representations of EM and WM by unveiling a duality between storing memories in synapses versus neural activity. This results in a formalism of prefrontal WM as structured, controllable neural subspaces (activity slots) representing dynamic cognitive maps without synaptic plasticity. Using neural networks, we elucidate differences, similarities, and trade-offs between the hippocampal and prefrontal algorithms. Lastly, we show that prefrontal representations in tasks from list learning to cue-dependent recall are unified as controllable activity slots. Our results unify frontal and temporal representations of memory and offer a new understanding for dynamic prefrontal representations of WM.