Papers by David Vállez García
![Research paper thumbnail of Pharmacokinetic modeling of [11C]flumazenil kinetics in the rat brain](https://attachments.academia-assets.com/52397576/thumbnails/1.jpg)
Background:
Preferred models for the pharmacokinetic analysis of [11C]flumazenil human studies ha... more Background:
Preferred models for the pharmacokinetic analysis of [11C]flumazenil human studies have been previously established. However, direct translation of these models and settings to animal studies might be sub-optimal. Therefore, this study evaluates pharmacokinetic models for the quantification of [11C]flumazenil binding in the rat brain. Dynamic (60 min) [11C]flumazenil brain PET scans were performed in two groups of male Wistar rats (tracer dose (TD), n = 10 and pre-saturated (PS), n = 2). Time-activity curves from five regions were analyzed, including the pons (pseudo-reference region). Distribution volume (Vt) was calculated using one-and two-tissue compartment models (1TCM and 2TCM) and spectral analysis (SA). Binding potential (BPnd) was determined from full and simplified reference tissue models with one or two compartments for the reference tissue (FRTM, SRTM, and SRTM-2C). Model preference was determined by Akaike information criterion (AIC), while parameter agreement was assessed by linear regression, repeated measurements ANOVA and Bland-Altman plots.
Results:
1TCM and 2TCM fits of regions with high specific binding showed similar AIC, a preference for the 1TCM, and good Vt agreement (0.1% difference). In contrast, the 2TCM was markedly preferred and necessary for fitting low specific-binding regions, where a worse Vt agreement (17.6% difference) and significant VT differences between the models (p < 0.005) were seen. The PS group displayed results similar to those of low specific-binding regions. All reference models (FRTM, SRTM, and SRTM-2C) resulted in at least 13% underestimation of BPnd.
Conclusions:
Although the 1TCM was sufficient for the quantification of high specific-binding regions, the 2TCM was found to be the most adequate for the quantification of [11C]flumazenil in the rat brain based on (1) higher fit quality, (2) lower AIC values, and (3) ability to provide reliable fits for all regions. Reference models resulted in negatively biased BPnd and were affected by specific binding in the pons of the rat.
Fingolimod was the first oral drug approved for
multiple sclerosis treatment. Its principal mecha... more Fingolimod was the first oral drug approved for
multiple sclerosis treatment. Its principal mechanism of action
is blocking of lymphocyte trafficking. In addition, recent studies
have shown its capability to diminish microglia activation.
The effect of preventive and curative fingolimod treatment on
the time-course of neuroinflammation was investigated in the
experimental autoimmune encephalomyelitis rat model for
multiple sclerosis. Neuroinflammatory progression was
followed in Dark Agouti female rats after immunization.
Positron-Emission tomography (PET) imaging with
(R)-[11C]PK11195 was performed on day 11, 15, 19, 27, 29
and 34 during normal disease progression, preventive and
curative treatments with fingolimod (1 mg/kg/day).
Additionally, bodyweight and clinical symptoms were determined.
Preventive treatment diminished bodyweight loss and
inhibited the appearance of neurological symptoms. In nontreated
rats, PET showed that neuroinflammation peaked in
the brainstem at day 19, whereas the imaging signal was decreased
in cortical regions. Both preventive and curative treatment
reduced neuroinflammation in the brainstem at day 19.
Eight days after treatment withdrawal, neuroinflammation had
flared-up, especially in cortical regions. Preventive treatment
with fingolimod suppressed clinical symptoms and neuroinflammation
in the brainstem. After treatment withdrawal, clinical
symptoms reappeared together with neuroinflammation in
cortical regions, suggesting a different pathway of disease
progression.
![Research paper thumbnail of Contribution of neuroinflammation to changes in [11C]flumazenil binding in the rat brain: Evaluation of the inflamed pons as reference tissue](https://attachments.academia-assets.com/52397474/thumbnails/1.jpg)
Introduction:
[11C]Flumazenil is a well–known PET tracer for GABA A receptors and is mainly used ... more Introduction:
[11C]Flumazenil is a well–known PET tracer for GABA A receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABA A receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue.
Methods:
The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6–7 days post-infection of male Wistar rats (HSE, n = 5 and control, n = 6). Additionally, the GABA A receptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling.
Results:
No statistically significant differences were found in the volume of distribution (Vt) or non-displaceable binding potential (BPnd) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil Vt in all brain regions. The BPnd obtained from SRTM exhibited a good correlation to DVR – 1 values from the two-tissue compartment model, coupled with some level of underestimation.
Conclusion:
Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation.
![Research paper thumbnail of Novel Approach to Repeated Arterial Blood Sampling in Small Animal PET: Application in a Test-Retest Study with the Adenosine A1 Receptor Ligand [11C]MPDX](https://attachments.academia-assets.com/50497383/thumbnails/1.jpg)
Purpose: Small animal positron emission tomography (PET) can be used to detect small changes in n... more Purpose: Small animal positron emission tomography (PET) can be used to detect small changes in neuroreceptor availability. This often requires rapid arterial blood sampling. However, current catheterization procedures do not allow repeated blood sampling. We have developed a procedure which allows arterial sampling on repeated occasions in the same animal.
Procedures: Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [11C]MPDX and blood sampling. PET images were co-registered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (Vt) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week.
Results: Surgery was successful in 90 % of the cases, and discomfort was minor. The Vt data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects.
Conclusion: Repeated quantitative imaging with a high reproducibility is possible with this approach.
There is increasing evidence of central hyperexcitability in chronic whiplash-associated disorder... more There is increasing evidence of central hyperexcitability in chronic whiplash-associated disorders (cWAD). However, little is known about how an apparently simple cervical spine injury can induce changes in cerebral processes. The present study was designed (1) to validate previous results showing alterations of regional cerebral blood flow (rCBF) in cWAD, (2) to test if central hyperexcitability reflects changes in rCBF upon non-painful stimulation of the neck, and (3) to verify our hypothesis that the missing link in understanding the underlying pathophysiology could be the close interaction between the neck and midbrain structures. For this purpose, alterations of rCBF were explored in a case-control study using H215O positron emission tomography, where each group was exposed to four different conditions, including rest and different levels of non-painful electrical stimulation of the neck. rCBF was found to be elevated in patients with cWAD in the posterior cingulate and precuneus, and decreased in the superior temporal, parahippocampal, and inferior frontal gyri, the thalamus and the insular cortex when compared with rCBF in healthy controls. No differences in rCBF were observed between different levels of electrical stimulation. The alterations in regions directly involved with pain perception and interoceptive processing indicate that cWAD symptoms might be the consequence of a mismatch during the integration of information in brain regions involved in pain processing.
11C-PBR28 is a second generation TSPO tracer with supposedly superior characteristics than the mo... more 11C-PBR28 is a second generation TSPO tracer with supposedly superior characteristics than the most commonly used tracer for neuroinflammation, (R)-11C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of 11C-PBR28 in rodent models of neuroinflammation have been published yet. Therefore, this study aims to evaluate 11C-PBR28 as a tool for detection and quantification of neuroinflammation in pre-clinical research and to compare its imaging properties with (R)-11C-PK11195. The herpes simplex encephalitis (HSE) model was used for induction of neuroinflammation in male Wistar rats. Six or seven days after virus inoculation, a dynamic 11C-PBR28 or (R)-11C-PK11195 PET scan with arterial blood sampling was performed. Pharmacokinetic modeling was performed on the PET data and analyzed using volumes of interest (VOIs) and voxel-based approach. VOI- and voxel-based analysis of 11C-PBR28 images showed overexpression of TSPO in brain regions known to be affected in the HSE rat model. 11C-PBR28 was metabolized faster than (R)-11C-PK11195, with a metabolic half-life in plasma of 5 and 21 min, respectively. Overall, 11C-PBR28 was more sensitive than (R)-11C-PK11195 in detecting neuroinflammation. The binding potential (BPND) of 11C-PBR28 was significantly higher (P < 0.05) in the medulla (176%), pons (146%), midbrain (101%), hippocampus (85%), thalamus (73%), cerebellum (54%) and hypothalamus (49%) in HSE rats than in control rats, while (R)-11C-PK11195 only showed a higher BPND in the medulla (32%). The BPND in control animals was not significantly different between tracers, suggesting that non-specific binding of both tracers is similar. 11C-PBR28 was more sensitive than (R)-11C-PK11195 in the detection of TSPO overexpression in the HSE rat model, as more brain regions with significantly increased tracer uptake could be found, irrespective of the data analysis method used. These results suggest that 11C-PBR28 should be able to detect more subtle changes in microglia activation in pre-clinical models of neuroinflammation.
Mild traumatic brain injury (mTBI) is the most common cause of head trauma. However, the time cou... more Mild traumatic brain injury (mTBI) is the most common cause of head trauma. However, the time course of functional pathology is not well defined. The purpose of this study was to evaluate the consequences of mTBI in rats over a period of 3 months, by determining the presence of neuroinflammation ([11C]PK11195) and changes in brain metabolism ([18F]FDG) with PET imaging. Male Sprague-Dawley rats were divided in mTBI (n=8) and sham (n=8) groups. In vivo PET imaging and behavioral tests (open field, object recognition and Y-maze) were performed at different time points after induction of the trauma. Differences between groups in PET images were explored using volume-of-interest and voxel-based analysis. mTBI did not result in death, skull fracture or suppression of reflexes. Weight gain was reduced (p=0.003) in the mTBI group as compared to the sham-treated group. No statistical differences were found in the behavioral tests at any time point. Volume-of-interest analysis showed neuroinflammation limited to the sub-acute phase (day 12) involving amygdala, globus pallidus, hypothalamus, pons, septum, striatum and thalamus (p<0.03, d>1.2). Alterations in glucose metabolism were detected over the 3 months period, with increased uptake in the medulla (p<0.04, d≥1.2), and decreased uptake in the globus pallidus, striatum and thalamus (p<0.04, d≤-1.2). Similar findings were observed in the voxel-based analysis (p<0.05 at cluster level). As a consequence of the mTBI, and in the absence of apparent behavioral changes, long-term relative brain glucose metabolism alterations were found in several brain regions, which mostly correspond with those presenting neuroinflammation in the sub-acute stage.
High-resolution anatomical image data in preclinical brain PET and SPECT studies is often not ava... more High-resolution anatomical image data in preclinical brain PET and SPECT studies is often not available, and inter-modality spatial normalization to an MRI brain template is frequently performed. However, this procedure can be challenging for tracers where substantial anatomical structures present limited tracer uptake. Therefore, we constructed and validated strain- and tracer-specific rat brain templates in Paxinos space to allow intra-modal registration. PET [18F]FDG, [11C]flumazenil, [11C]MeDAS, [11C]PK11195 and [11C]raclopride, and SPECT [99mTc]HMPAO brain scans were acquired from healthy male rats. Tracer-specific templates were constructed by averaging the scans, and by spatial normalization to a widely used MRI-based template. The added value of tracer-specific templates was evaluated by quantification of the residual error between original and realigned voxels after random misalignments of the data set. Additionally, the impact of strain differences, disease uptake patterns (focal and diffuse lesion), and the effect of image and template size on the registration errors were explored. Mean registration errors were 0.70±0.32mm for [18F]FDG (n = 25), 0.23±0.10mm for [11C]flumazenil (n = 13), 0.88±0.20 mm for [11C]MeDAS (n = 15), 0.64±0.28mm for [11C]PK11195 (n = 19), 0.34±0.15mm for [11C]raclopride (n = 6), and 0.40±0.13mm for [99mTc]HMPAO (n = 15). These values were smallest with tracer-specific templates, when compared to the use of [18F]FDG as reference template (p<0.001). Additionally, registration errors were smallest with strain-specific templates (p<0.05), and when images and templates had the same size (p≤0.001). Moreover, highest registration errors were found for the focal lesion group (p<0.005) and the diffuse lesion group (p = n.s.). In the voxel-based analysis, the reported coordinates of the focal lesion model are consistent with the stereotaxic injection procedure. The use of PET/SPECT strain- and tracer-specific templates allows accurate registration of functional rat brain data, independent of disease specific uptake patterns and with registration error below spatial resolution of the cameras. The templates and the SAMIT package will be freely available for the research community.
![Research paper thumbnail of Evaluation of [11C]CB184 for imaging and quantification of TSPO overexpression in rat model of herpes encephalitis](https://attachments.academia-assets.com/37600163/thumbnails/1.jpg)
Purpose
Evaluation of the translocator protein (TSPO) overexpression is considered an attractive... more Purpose
Evaluation of the translocator protein (TSPO) overexpression is considered an attractive research tool for monitoring neuroinflammation in several neurological and psychiatric disorders. [11C]PK11195 PET imaging has been widely used for this purpose. However, it has a low sensitivity and a poor signal-to-noise ratio. For these reasons, [11C]CB184 was evaluated as a potentially more sensitive PET tracer.
Methods
A model of herpes simplex encephalitis (HSE) was induced in male Wistar rats. On day 6 or 7 after virus inoculation, [11C]CB184 PET scans were acquired followed by ex vivo evaluation of biodistribution. In addition, [11C]CB184 and [11C]PK11195 PET scans with arterial blood sampling were acquired to generate input for pharmacokinetic modelling. Differences between the saline-treated control group and the virus-treated HSE group were explored using volumes of interest and voxel-based analysis.
Results
The biodistribution study showed significantly higher [11C]CB184 uptake in the amygdala, olfactory bulb, medulla, pons, and striatum (p < 0.05) in HSE rats than in controls rats, and the voxel-based analysis showed higher bilateral uptake in the pons and medulla (p < 0.05, corrected at cluster level). A high correlation was found between tracer uptake in the biodistribution study and on the PET scans (p < 0.001, r2=0.71). Pretreatment with 5 mg/kg of unlabeled PK11195 effectively reduced (p < 0.001) [11C]CB184 uptake in the whole brain. Both tracers, [11C]CB184 and [11C]PK11195, showed similar amounts of metabolites in plasma, and the binding potential (BPND) was not significantly different between the HSE rats and the control rats. In HSE rats BPND for [11C]CB184 was significantly higher (p < 0.05) in the amygdala, hypothalamus, medulla, pons, and septum than in control rats, whereas higher uptake of [11C]PK11195 was only detected in the medulla.
Conclusion
[11C]CB184 showed nonspecific binding to healthy tissue comparable to that observed for [11C]PK11195, but it displayed significantly higher specific binding in those brain regions affected by the HSE. Our results suggest that [11C]CB184 PET is a good alternative for imaging of neuroinflammatory processes.
Conference Presentations by David Vállez García
![Research paper thumbnail of Three Months Follow-Up of Mild Traumatic Brain Injury in Rats: A Combined [18F]FDG and [11C]PK11195 PET Study](https://attachments.academia-assets.com/39523348/thumbnails/1.jpg)
Annual Congress of the European Association of Nuclear Medicine (EANM'15)
Aim: Mild traumatic brain injury (mTBI) is the most common cause of head trauma and it is especia... more Aim: Mild traumatic brain injury (mTBI) is the most common cause of head trauma and it is especially relevant in adolescents and sport activities. However, the time course of its functional pathology is not well defined. In this study the consequences of mTBI were evaluated in a rat model over a period of 3 months. The presence of neuroinflammation ([11C]PK11195) and changes in brain metabolism([18F]FDG) were determined using small animal PET imaging.
Material and Methods: A weight-drop mTBI model was used to replicate the pathological features seen in humans. Male Sprague-Dawley rats were divided into sham (n=8) and trauma (n=8) groups. PET imaging and behavioral tests (i.e. open field, object recognition and Y-maze) were performed at different time points after induction of the trauma: acute stage (9-12 days), 1 and 3 months. Differences between groups in the bodyweight and behavioral scores were analyzed using the Generalized Estimating Equations model and p<0.05 were considered significant. Differences in tracer uptake were analyzed with a voxel-based analysis. T-maps were interrogated with uncorrected p<0.005 and 200 threshold voxels; only clusters with FDR-corrected p<0.05 were considered significant.
Results: Trauma induction did not result in death, skull fracture or neurological suppression of reflexes. A statistically significant decrease in gained body weight was observed in mTBI group (p=0.003). No statistical differences were found between groups in any of the behavioral tests. In the voxel-based analysis, a comparison between mTBI and sham groups was performed at each time point. A neuroinflammatory process was detected only in the acute phase, with significantly
higher [11C]PK11195 uptake located bilaterally in the pons, medulla, cerebellum, hypothalamus, caudate, putamen, and the right amygdala. Increased regional [18F]FDG uptake in mTBI rats was detected in all time points bilaterally in the medulla, in addition to an increased uptake at 3 months in the left motor, somatosensory, visual and parietal cortices. Moreover, decreased uptake was detected during the follow-up period in the thalamus, internal capsule, amygdala, caudate, putamen, globus pallidus, hippocampus, and somatosensory cortex.
Conclusion: Alterations in the regional glucose metabolism of the brain extend for a period of at least 3 months in regions that seem to present an acute neuroinflammatory response to the trauma. The presence of these long-lasting functional alterations must be considered carefully in the context of mTBI, especially in sports and recreational activities where patients may be exposed to a repeated head trauma.
Objectives: Template based spatial co-registration of PET and SPECT data is an important first st... more Objectives: Template based spatial co-registration of PET and SPECT data is an important first step in its semi- automatic processing, facilitating VOI- and voxel-based analysis. Although this procedure is standard in human, using corresponding MRI images, these systems are often not accessible for preclinical research. Alternatively, manual co-registration of images to a MRI template is often performed. However, this is operator dependent and can introduce bias. Therefore, we constructed several tracer-specific PET and SPECT rat brain templates for automatic co-registration, spatially aligned with a widely used MRI-based template in Paxinos stereotactic space [1]. Methods: PET (18F-FDG, 11C-PK11195, and 11C-MeDAS) and SPECT (99mTc-HMPAO) brain scans were acquired from healthy male Sprague-Dawley and Wistar rats. Symmetrical left-right templates were constructed by averaging the scans. Within-modality registration was performed by minimizing the sum of squared difference and template to MRI registration by normalized mutual information maximization algorithm. For validation purposes, PET scans were acquired from a rat model of multiple sclerosis (MS) where focal demyelination was induced by injection of lysolecithin (or control saline) in right corpus callosum and striatum. Parametric SUV images were created for automatic co-registration. The validity of the templates was assessed by estimation of registration accuracy errors, inter-subject variability, right-to-left asymmetry indices, and voxel-based analysis of the MS model [2]. Results: The obtained mean registration errors were 0.097-1.277mm for PET, and 0.059-0.477mm for SPECT. These values are below spatial resolution of the cameras (1.4mm and 0.8mm, respectively) and in agreement with human literature [3]. Results from voxel-based analyses (Figure 1) correspond with those previously reported using VOI-based analysis [4], and correlate with the regions where lesion was induced. Conclusion: The constructed tracer-specific templates allow accurate registration of functional rat brain data, using automatic normalization algorithms available in standard packages (e.g., SPM, FSL), supporting either VOI- or voxel-based analysis. The templates will be made freely available for the research community.
Aim:
In vivo evaluation of microglia activation and neuroinflammation is considered a potential ... more Aim:
In vivo evaluation of microglia activation and neuroinflammation is considered a potential tool in the management of several neurological and psychiatric disorders. [11C]PK11195 has been widely used for this purpose in PET imaging. However, it possesses a low sensitivity and poor signal-to-noise ratio. For that reason, [11C]CB184 was evaluated as a potential more sensitive PET tracer, using a rat model of herpes encephalitis.
Materials and methods:
Male Wistar rats were intranasal inoculated with HSV-1 (HSE) or PBS (control). At either day 6 or 7 after inoculation, [11C]CB184 PET scans were acquired, followed by ex vivo biodistribution. Arterial blood sampling of [11C]CB184 and [11C]PK11195 scans was performed for pharmacokinetic modelling. Differences between control and HSE groups were explored using volumes of interest and voxel-based analysis.
Results:
The ex vivo uptake of [11C]CB184 in HSE rats, as compared with control, was significantly increased (p<0.05) in amygdala (73%), bulbus olfactorius (43%), medulla (156%), pons (100%), and striatum (60%). Pre-treatment with unlabeled PK11195 effectively reduced [11C]CB184 uptake in whole brain of control and HSE rats (p<0.001). A high correlation was found between biodistribution and PET SUV values (p<0.001, r2=0.71). [11C]CB184 voxel-based analysis showed an increased bilateral uptake in pons and medulla (cluster level p<0.05, corrected for family-wise error). When comparing [11C]CB184 with [11C]PK11195, a significant higher plasma peak was found in the distribution phase of [11C]CB184 (p<0.01 at 45-75s after injection). Metabolites of [11C]CB184 hardly crossed the blood brain barrier (1.2-1.3%). Both tracers showed a similar metabolic rate. The pharmacokinetics of [11C]CB184 showed a good fit to Logan and two-tissue compartment model (reversible binding). The later was used to calculate the binding potential (k3/k4). No statistical difference was found between [11C]CB184 and [11C]PK11195 in the control group. However, when comparing HSE with control rats, an increased [11C]CB184 uptake (p<0.05) was found in amygdala (49%), hypothalamus (69%), medulla (93%), pons (70%), and septum (77%), whereas increased [11C]PK11195 uptake was only found in medulla (55%).
Conclusion:
[11C]CB184 showed a high and specific ex vivo and in vivo uptake in the encephalitic rat brain. The non-specific binding of the tracer to healthy tissue is comparable to that observed in [11C]PK11195, but it displayed a significantly higher uptake for those brain regions affected by the herpes encephalitis. Our results suggest that [11C]CB184 is a good alternative for the imaging of neuroinflammatory processes.
Correspondence by David Vállez García
Book Chapter by David Vállez García
Nuclear Medicine and Radiologic Imaging in Sports Injuries, 2015
Concussions in sports and during recreational activities are a major source of traumatic brain in... more Concussions in sports and during recreational activities are a major source of traumatic brain injury in our society. This is mainly relevant in adolescence and young adulthood, where the annual rate of diagnosed concussions is increasing from year to year. Contact sports (e.g., ice hockey, American football, or boxing) are especially exposed to repeated concussions. While most of the athletes recover fully from the trauma, some experience a variety of symptoms including headache, fatigue, dizziness, anxiety, abnormal balance and postural instability, impaired memory, or other cognitive deficits. Moreover, there is growing evidence regarding clinical and neuropathological consequences of repetitive concussions, which are also linked to an increased risk for depression and Alzheimer’s disease or the development of chronic traumatic encephalopathy. With little contribution of conventional structural imaging (computed tomography (CT) or magnetic resonance imaging (MRI)) to the evaluation of concussion, nuclear imaging techniques (i.e., positron emission tomography (PET) and single-photon emission computed tomography (SPECT)) are in a favorable position to provide reliable tools for a better understanding of the pathophysiology and the clinical evaluation of athletes suffering a concussion.
PET and SPECT in Neurology, 2014
Whiplash-associated disorder (WAD) describes a heterogeneous group of symptoms, which develops fr... more Whiplash-associated disorder (WAD) describes a heterogeneous group of symptoms, which develops frequently after an unexpected rear-end car collision. In some of these patients, the symptoms persist for years. There is an ongoing scientific debate about the existence of tissue injury to support this disorder, due to the lack of findings with current diagnostic techniques and the prevalence of emotional traits as risk factors. The purpose of this chapter is to (1) overview the scientific data regarding the presence of an injury mechanism as a consequence of the whiplash trauma, (2) remark the unexpectedness of the accident as essential, and (3) present a new concept according to which WAD symptoms are the result of a mismatch between aberrant information from the cervical spinal cord and the information from the vestibular and visual systems, all of which are integrated in the mesencephalic periaqueductal gray and adjoining regions.
PET and SPECT in Neurology, 2014
This chapter provides an up-to-date review of nuclear medicine neuroimaging in traumatic brain in... more This chapter provides an up-to-date review of nuclear medicine neuroimaging in traumatic brain injury (TBI). 18F-FDG PET will remain a valuable tool in researching complex mechanisms associated with early metabolic dysfunction in TBI. Although evidence-based imaging studies are needed, 18F-FDG PET in the TBI acute phase appeared to be more useful in those patients in whom structural neuroimages fail to show abnormalities explaining their neurological state. 15O2-PET is also a solid technique for research in acute TBI, but in contrast to 18F-FDG PET it is not widely available due to its high cost. In the chronic TBI phase, most 18F-FDG PET studies converge to identify a diffuse cortical–subcortical hypometabolism involving key regions for cognitive function. Recent studies suggest the usefulness of 18F-FDG PET for the evaluation of therapeutic interventions in chronic TBI patients with cognitive deficits. In recent years, interest in studying cell-specific processes is growing. The use of radioligands as markers of neuroinflammation could become attractive for detecting secondary damage and serve for the evaluation of different therapeutic approaches. SPECT advances also make this technique a valid alternative for the study of TBI.
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Papers by David Vállez García
Preferred models for the pharmacokinetic analysis of [11C]flumazenil human studies have been previously established. However, direct translation of these models and settings to animal studies might be sub-optimal. Therefore, this study evaluates pharmacokinetic models for the quantification of [11C]flumazenil binding in the rat brain. Dynamic (60 min) [11C]flumazenil brain PET scans were performed in two groups of male Wistar rats (tracer dose (TD), n = 10 and pre-saturated (PS), n = 2). Time-activity curves from five regions were analyzed, including the pons (pseudo-reference region). Distribution volume (Vt) was calculated using one-and two-tissue compartment models (1TCM and 2TCM) and spectral analysis (SA). Binding potential (BPnd) was determined from full and simplified reference tissue models with one or two compartments for the reference tissue (FRTM, SRTM, and SRTM-2C). Model preference was determined by Akaike information criterion (AIC), while parameter agreement was assessed by linear regression, repeated measurements ANOVA and Bland-Altman plots.
Results:
1TCM and 2TCM fits of regions with high specific binding showed similar AIC, a preference for the 1TCM, and good Vt agreement (0.1% difference). In contrast, the 2TCM was markedly preferred and necessary for fitting low specific-binding regions, where a worse Vt agreement (17.6% difference) and significant VT differences between the models (p < 0.005) were seen. The PS group displayed results similar to those of low specific-binding regions. All reference models (FRTM, SRTM, and SRTM-2C) resulted in at least 13% underestimation of BPnd.
Conclusions:
Although the 1TCM was sufficient for the quantification of high specific-binding regions, the 2TCM was found to be the most adequate for the quantification of [11C]flumazenil in the rat brain based on (1) higher fit quality, (2) lower AIC values, and (3) ability to provide reliable fits for all regions. Reference models resulted in negatively biased BPnd and were affected by specific binding in the pons of the rat.
multiple sclerosis treatment. Its principal mechanism of action
is blocking of lymphocyte trafficking. In addition, recent studies
have shown its capability to diminish microglia activation.
The effect of preventive and curative fingolimod treatment on
the time-course of neuroinflammation was investigated in the
experimental autoimmune encephalomyelitis rat model for
multiple sclerosis. Neuroinflammatory progression was
followed in Dark Agouti female rats after immunization.
Positron-Emission tomography (PET) imaging with
(R)-[11C]PK11195 was performed on day 11, 15, 19, 27, 29
and 34 during normal disease progression, preventive and
curative treatments with fingolimod (1 mg/kg/day).
Additionally, bodyweight and clinical symptoms were determined.
Preventive treatment diminished bodyweight loss and
inhibited the appearance of neurological symptoms. In nontreated
rats, PET showed that neuroinflammation peaked in
the brainstem at day 19, whereas the imaging signal was decreased
in cortical regions. Both preventive and curative treatment
reduced neuroinflammation in the brainstem at day 19.
Eight days after treatment withdrawal, neuroinflammation had
flared-up, especially in cortical regions. Preventive treatment
with fingolimod suppressed clinical symptoms and neuroinflammation
in the brainstem. After treatment withdrawal, clinical
symptoms reappeared together with neuroinflammation in
cortical regions, suggesting a different pathway of disease
progression.
[11C]Flumazenil is a well–known PET tracer for GABA A receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABA A receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue.
Methods:
The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6–7 days post-infection of male Wistar rats (HSE, n = 5 and control, n = 6). Additionally, the GABA A receptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling.
Results:
No statistically significant differences were found in the volume of distribution (Vt) or non-displaceable binding potential (BPnd) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil Vt in all brain regions. The BPnd obtained from SRTM exhibited a good correlation to DVR – 1 values from the two-tissue compartment model, coupled with some level of underestimation.
Conclusion:
Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation.
Procedures: Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [11C]MPDX and blood sampling. PET images were co-registered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (Vt) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week.
Results: Surgery was successful in 90 % of the cases, and discomfort was minor. The Vt data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects.
Conclusion: Repeated quantitative imaging with a high reproducibility is possible with this approach.
Evaluation of the translocator protein (TSPO) overexpression is considered an attractive research tool for monitoring neuroinflammation in several neurological and psychiatric disorders. [11C]PK11195 PET imaging has been widely used for this purpose. However, it has a low sensitivity and a poor signal-to-noise ratio. For these reasons, [11C]CB184 was evaluated as a potentially more sensitive PET tracer.
Methods
A model of herpes simplex encephalitis (HSE) was induced in male Wistar rats. On day 6 or 7 after virus inoculation, [11C]CB184 PET scans were acquired followed by ex vivo evaluation of biodistribution. In addition, [11C]CB184 and [11C]PK11195 PET scans with arterial blood sampling were acquired to generate input for pharmacokinetic modelling. Differences between the saline-treated control group and the virus-treated HSE group were explored using volumes of interest and voxel-based analysis.
Results
The biodistribution study showed significantly higher [11C]CB184 uptake in the amygdala, olfactory bulb, medulla, pons, and striatum (p < 0.05) in HSE rats than in controls rats, and the voxel-based analysis showed higher bilateral uptake in the pons and medulla (p < 0.05, corrected at cluster level). A high correlation was found between tracer uptake in the biodistribution study and on the PET scans (p < 0.001, r2=0.71). Pretreatment with 5 mg/kg of unlabeled PK11195 effectively reduced (p < 0.001) [11C]CB184 uptake in the whole brain. Both tracers, [11C]CB184 and [11C]PK11195, showed similar amounts of metabolites in plasma, and the binding potential (BPND) was not significantly different between the HSE rats and the control rats. In HSE rats BPND for [11C]CB184 was significantly higher (p < 0.05) in the amygdala, hypothalamus, medulla, pons, and septum than in control rats, whereas higher uptake of [11C]PK11195 was only detected in the medulla.
Conclusion
[11C]CB184 showed nonspecific binding to healthy tissue comparable to that observed for [11C]PK11195, but it displayed significantly higher specific binding in those brain regions affected by the HSE. Our results suggest that [11C]CB184 PET is a good alternative for imaging of neuroinflammatory processes.
Conference Presentations by David Vállez García
Material and Methods: A weight-drop mTBI model was used to replicate the pathological features seen in humans. Male Sprague-Dawley rats were divided into sham (n=8) and trauma (n=8) groups. PET imaging and behavioral tests (i.e. open field, object recognition and Y-maze) were performed at different time points after induction of the trauma: acute stage (9-12 days), 1 and 3 months. Differences between groups in the bodyweight and behavioral scores were analyzed using the Generalized Estimating Equations model and p<0.05 were considered significant. Differences in tracer uptake were analyzed with a voxel-based analysis. T-maps were interrogated with uncorrected p<0.005 and 200 threshold voxels; only clusters with FDR-corrected p<0.05 were considered significant.
Results: Trauma induction did not result in death, skull fracture or neurological suppression of reflexes. A statistically significant decrease in gained body weight was observed in mTBI group (p=0.003). No statistical differences were found between groups in any of the behavioral tests. In the voxel-based analysis, a comparison between mTBI and sham groups was performed at each time point. A neuroinflammatory process was detected only in the acute phase, with significantly
higher [11C]PK11195 uptake located bilaterally in the pons, medulla, cerebellum, hypothalamus, caudate, putamen, and the right amygdala. Increased regional [18F]FDG uptake in mTBI rats was detected in all time points bilaterally in the medulla, in addition to an increased uptake at 3 months in the left motor, somatosensory, visual and parietal cortices. Moreover, decreased uptake was detected during the follow-up period in the thalamus, internal capsule, amygdala, caudate, putamen, globus pallidus, hippocampus, and somatosensory cortex.
Conclusion: Alterations in the regional glucose metabolism of the brain extend for a period of at least 3 months in regions that seem to present an acute neuroinflammatory response to the trauma. The presence of these long-lasting functional alterations must be considered carefully in the context of mTBI, especially in sports and recreational activities where patients may be exposed to a repeated head trauma.
In vivo evaluation of microglia activation and neuroinflammation is considered a potential tool in the management of several neurological and psychiatric disorders. [11C]PK11195 has been widely used for this purpose in PET imaging. However, it possesses a low sensitivity and poor signal-to-noise ratio. For that reason, [11C]CB184 was evaluated as a potential more sensitive PET tracer, using a rat model of herpes encephalitis.
Materials and methods:
Male Wistar rats were intranasal inoculated with HSV-1 (HSE) or PBS (control). At either day 6 or 7 after inoculation, [11C]CB184 PET scans were acquired, followed by ex vivo biodistribution. Arterial blood sampling of [11C]CB184 and [11C]PK11195 scans was performed for pharmacokinetic modelling. Differences between control and HSE groups were explored using volumes of interest and voxel-based analysis.
Results:
The ex vivo uptake of [11C]CB184 in HSE rats, as compared with control, was significantly increased (p<0.05) in amygdala (73%), bulbus olfactorius (43%), medulla (156%), pons (100%), and striatum (60%). Pre-treatment with unlabeled PK11195 effectively reduced [11C]CB184 uptake in whole brain of control and HSE rats (p<0.001). A high correlation was found between biodistribution and PET SUV values (p<0.001, r2=0.71). [11C]CB184 voxel-based analysis showed an increased bilateral uptake in pons and medulla (cluster level p<0.05, corrected for family-wise error). When comparing [11C]CB184 with [11C]PK11195, a significant higher plasma peak was found in the distribution phase of [11C]CB184 (p<0.01 at 45-75s after injection). Metabolites of [11C]CB184 hardly crossed the blood brain barrier (1.2-1.3%). Both tracers showed a similar metabolic rate. The pharmacokinetics of [11C]CB184 showed a good fit to Logan and two-tissue compartment model (reversible binding). The later was used to calculate the binding potential (k3/k4). No statistical difference was found between [11C]CB184 and [11C]PK11195 in the control group. However, when comparing HSE with control rats, an increased [11C]CB184 uptake (p<0.05) was found in amygdala (49%), hypothalamus (69%), medulla (93%), pons (70%), and septum (77%), whereas increased [11C]PK11195 uptake was only found in medulla (55%).
Conclusion:
[11C]CB184 showed a high and specific ex vivo and in vivo uptake in the encephalitic rat brain. The non-specific binding of the tracer to healthy tissue is comparable to that observed in [11C]PK11195, but it displayed a significantly higher uptake for those brain regions affected by the herpes encephalitis. Our results suggest that [11C]CB184 is a good alternative for the imaging of neuroinflammatory processes.
Correspondence by David Vállez García
Book Chapter by David Vállez García
Preferred models for the pharmacokinetic analysis of [11C]flumazenil human studies have been previously established. However, direct translation of these models and settings to animal studies might be sub-optimal. Therefore, this study evaluates pharmacokinetic models for the quantification of [11C]flumazenil binding in the rat brain. Dynamic (60 min) [11C]flumazenil brain PET scans were performed in two groups of male Wistar rats (tracer dose (TD), n = 10 and pre-saturated (PS), n = 2). Time-activity curves from five regions were analyzed, including the pons (pseudo-reference region). Distribution volume (Vt) was calculated using one-and two-tissue compartment models (1TCM and 2TCM) and spectral analysis (SA). Binding potential (BPnd) was determined from full and simplified reference tissue models with one or two compartments for the reference tissue (FRTM, SRTM, and SRTM-2C). Model preference was determined by Akaike information criterion (AIC), while parameter agreement was assessed by linear regression, repeated measurements ANOVA and Bland-Altman plots.
Results:
1TCM and 2TCM fits of regions with high specific binding showed similar AIC, a preference for the 1TCM, and good Vt agreement (0.1% difference). In contrast, the 2TCM was markedly preferred and necessary for fitting low specific-binding regions, where a worse Vt agreement (17.6% difference) and significant VT differences between the models (p < 0.005) were seen. The PS group displayed results similar to those of low specific-binding regions. All reference models (FRTM, SRTM, and SRTM-2C) resulted in at least 13% underestimation of BPnd.
Conclusions:
Although the 1TCM was sufficient for the quantification of high specific-binding regions, the 2TCM was found to be the most adequate for the quantification of [11C]flumazenil in the rat brain based on (1) higher fit quality, (2) lower AIC values, and (3) ability to provide reliable fits for all regions. Reference models resulted in negatively biased BPnd and were affected by specific binding in the pons of the rat.
multiple sclerosis treatment. Its principal mechanism of action
is blocking of lymphocyte trafficking. In addition, recent studies
have shown its capability to diminish microglia activation.
The effect of preventive and curative fingolimod treatment on
the time-course of neuroinflammation was investigated in the
experimental autoimmune encephalomyelitis rat model for
multiple sclerosis. Neuroinflammatory progression was
followed in Dark Agouti female rats after immunization.
Positron-Emission tomography (PET) imaging with
(R)-[11C]PK11195 was performed on day 11, 15, 19, 27, 29
and 34 during normal disease progression, preventive and
curative treatments with fingolimod (1 mg/kg/day).
Additionally, bodyweight and clinical symptoms were determined.
Preventive treatment diminished bodyweight loss and
inhibited the appearance of neurological symptoms. In nontreated
rats, PET showed that neuroinflammation peaked in
the brainstem at day 19, whereas the imaging signal was decreased
in cortical regions. Both preventive and curative treatment
reduced neuroinflammation in the brainstem at day 19.
Eight days after treatment withdrawal, neuroinflammation had
flared-up, especially in cortical regions. Preventive treatment
with fingolimod suppressed clinical symptoms and neuroinflammation
in the brainstem. After treatment withdrawal, clinical
symptoms reappeared together with neuroinflammation in
cortical regions, suggesting a different pathway of disease
progression.
[11C]Flumazenil is a well–known PET tracer for GABA A receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABA A receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue.
Methods:
The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6–7 days post-infection of male Wistar rats (HSE, n = 5 and control, n = 6). Additionally, the GABA A receptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling.
Results:
No statistically significant differences were found in the volume of distribution (Vt) or non-displaceable binding potential (BPnd) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil Vt in all brain regions. The BPnd obtained from SRTM exhibited a good correlation to DVR – 1 values from the two-tissue compartment model, coupled with some level of underestimation.
Conclusion:
Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation.
Procedures: Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [11C]MPDX and blood sampling. PET images were co-registered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (Vt) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week.
Results: Surgery was successful in 90 % of the cases, and discomfort was minor. The Vt data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects.
Conclusion: Repeated quantitative imaging with a high reproducibility is possible with this approach.
Evaluation of the translocator protein (TSPO) overexpression is considered an attractive research tool for monitoring neuroinflammation in several neurological and psychiatric disorders. [11C]PK11195 PET imaging has been widely used for this purpose. However, it has a low sensitivity and a poor signal-to-noise ratio. For these reasons, [11C]CB184 was evaluated as a potentially more sensitive PET tracer.
Methods
A model of herpes simplex encephalitis (HSE) was induced in male Wistar rats. On day 6 or 7 after virus inoculation, [11C]CB184 PET scans were acquired followed by ex vivo evaluation of biodistribution. In addition, [11C]CB184 and [11C]PK11195 PET scans with arterial blood sampling were acquired to generate input for pharmacokinetic modelling. Differences between the saline-treated control group and the virus-treated HSE group were explored using volumes of interest and voxel-based analysis.
Results
The biodistribution study showed significantly higher [11C]CB184 uptake in the amygdala, olfactory bulb, medulla, pons, and striatum (p < 0.05) in HSE rats than in controls rats, and the voxel-based analysis showed higher bilateral uptake in the pons and medulla (p < 0.05, corrected at cluster level). A high correlation was found between tracer uptake in the biodistribution study and on the PET scans (p < 0.001, r2=0.71). Pretreatment with 5 mg/kg of unlabeled PK11195 effectively reduced (p < 0.001) [11C]CB184 uptake in the whole brain. Both tracers, [11C]CB184 and [11C]PK11195, showed similar amounts of metabolites in plasma, and the binding potential (BPND) was not significantly different between the HSE rats and the control rats. In HSE rats BPND for [11C]CB184 was significantly higher (p < 0.05) in the amygdala, hypothalamus, medulla, pons, and septum than in control rats, whereas higher uptake of [11C]PK11195 was only detected in the medulla.
Conclusion
[11C]CB184 showed nonspecific binding to healthy tissue comparable to that observed for [11C]PK11195, but it displayed significantly higher specific binding in those brain regions affected by the HSE. Our results suggest that [11C]CB184 PET is a good alternative for imaging of neuroinflammatory processes.
Material and Methods: A weight-drop mTBI model was used to replicate the pathological features seen in humans. Male Sprague-Dawley rats were divided into sham (n=8) and trauma (n=8) groups. PET imaging and behavioral tests (i.e. open field, object recognition and Y-maze) were performed at different time points after induction of the trauma: acute stage (9-12 days), 1 and 3 months. Differences between groups in the bodyweight and behavioral scores were analyzed using the Generalized Estimating Equations model and p<0.05 were considered significant. Differences in tracer uptake were analyzed with a voxel-based analysis. T-maps were interrogated with uncorrected p<0.005 and 200 threshold voxels; only clusters with FDR-corrected p<0.05 were considered significant.
Results: Trauma induction did not result in death, skull fracture or neurological suppression of reflexes. A statistically significant decrease in gained body weight was observed in mTBI group (p=0.003). No statistical differences were found between groups in any of the behavioral tests. In the voxel-based analysis, a comparison between mTBI and sham groups was performed at each time point. A neuroinflammatory process was detected only in the acute phase, with significantly
higher [11C]PK11195 uptake located bilaterally in the pons, medulla, cerebellum, hypothalamus, caudate, putamen, and the right amygdala. Increased regional [18F]FDG uptake in mTBI rats was detected in all time points bilaterally in the medulla, in addition to an increased uptake at 3 months in the left motor, somatosensory, visual and parietal cortices. Moreover, decreased uptake was detected during the follow-up period in the thalamus, internal capsule, amygdala, caudate, putamen, globus pallidus, hippocampus, and somatosensory cortex.
Conclusion: Alterations in the regional glucose metabolism of the brain extend for a period of at least 3 months in regions that seem to present an acute neuroinflammatory response to the trauma. The presence of these long-lasting functional alterations must be considered carefully in the context of mTBI, especially in sports and recreational activities where patients may be exposed to a repeated head trauma.
In vivo evaluation of microglia activation and neuroinflammation is considered a potential tool in the management of several neurological and psychiatric disorders. [11C]PK11195 has been widely used for this purpose in PET imaging. However, it possesses a low sensitivity and poor signal-to-noise ratio. For that reason, [11C]CB184 was evaluated as a potential more sensitive PET tracer, using a rat model of herpes encephalitis.
Materials and methods:
Male Wistar rats were intranasal inoculated with HSV-1 (HSE) or PBS (control). At either day 6 or 7 after inoculation, [11C]CB184 PET scans were acquired, followed by ex vivo biodistribution. Arterial blood sampling of [11C]CB184 and [11C]PK11195 scans was performed for pharmacokinetic modelling. Differences between control and HSE groups were explored using volumes of interest and voxel-based analysis.
Results:
The ex vivo uptake of [11C]CB184 in HSE rats, as compared with control, was significantly increased (p<0.05) in amygdala (73%), bulbus olfactorius (43%), medulla (156%), pons (100%), and striatum (60%). Pre-treatment with unlabeled PK11195 effectively reduced [11C]CB184 uptake in whole brain of control and HSE rats (p<0.001). A high correlation was found between biodistribution and PET SUV values (p<0.001, r2=0.71). [11C]CB184 voxel-based analysis showed an increased bilateral uptake in pons and medulla (cluster level p<0.05, corrected for family-wise error). When comparing [11C]CB184 with [11C]PK11195, a significant higher plasma peak was found in the distribution phase of [11C]CB184 (p<0.01 at 45-75s after injection). Metabolites of [11C]CB184 hardly crossed the blood brain barrier (1.2-1.3%). Both tracers showed a similar metabolic rate. The pharmacokinetics of [11C]CB184 showed a good fit to Logan and two-tissue compartment model (reversible binding). The later was used to calculate the binding potential (k3/k4). No statistical difference was found between [11C]CB184 and [11C]PK11195 in the control group. However, when comparing HSE with control rats, an increased [11C]CB184 uptake (p<0.05) was found in amygdala (49%), hypothalamus (69%), medulla (93%), pons (70%), and septum (77%), whereas increased [11C]PK11195 uptake was only found in medulla (55%).
Conclusion:
[11C]CB184 showed a high and specific ex vivo and in vivo uptake in the encephalitic rat brain. The non-specific binding of the tracer to healthy tissue is comparable to that observed in [11C]PK11195, but it displayed a significantly higher uptake for those brain regions affected by the herpes encephalitis. Our results suggest that [11C]CB184 is a good alternative for the imaging of neuroinflammatory processes.