[18F]FDG PET metabolic patterns in mesial temporal lobe epilepsy with different pathological types.

OBJECTIVES: To investigate [18F]FDG PET patterns of mesial temporal lobe epilepsy (MTLE) patients with distinct pathologic types and provide possible guidance for predicting long-term prognoses of patients undergoing epilepsy surgery. METHODS: This was a retrospective review of MTLE patients who underwent anterior temporal lobectomy between 2016 and 2021. Patients were classified as having chronic inflammation and gliosis (gliosis, n = 44), hippocampal sclerosis (HS, n = 43), or focal cortical dysplasia plus HS (FCD-HS, n = 13) based on the postoperative pathological diagnosis. Metabolic patterns and the severity of metabolic abnormalities were investigated among MTLE patients and healthy controls (HCs). The standardized uptake value (SUV), SUV ratio (SUVr), and asymmetry index (AI) of regions of interest were applied to evaluate the severity of metabolic abnormalities. Imaging processing was performed with statistical parametric mapping (SPM12). RESULTS: With a mean follow-up of 2.8 years, the seizure freedom (Engel class IA) rates of gliosis, HS, and FCD-HS were 54.55%, 62.79%, and 69.23%, respectively. The patients in the gliosis group presented a metabolic pattern with a larger involvement of extratemporal areas, including the ipsilateral insula. SUV, SUVr, and AI in ROIs were decreased for patients in all three MTLE groups compared with those of HCs, but the differences among all three MTLE groups were not significant. CONCLUSIONS: MTLE patients with isolated gliosis had the worst prognosis and hypometabolism in the insula, but the degree of metabolic decrease did not differ from the other two groups. Hypometabolic regions should be prioritized for [18F]FDG PET presurgical evaluation rather than [18F]FDG uptake values. CLINICAL RELEVANCE STATEMENT: This study proposes guidance for optimizing the operation scheme in patients with refractory MTLE and emphasizes the potential of molecular neuroimaging with PET using selected tracers to predict the postsurgical histology of patients with refractory MTLE epilepsy. KEY POINTS: • MTLE patients with gliosis had poor surgical outcomes and showed a distinct pattern of decreased metabolism in the ipsilateral insula. • In the preoperative assessment of MTLE, it is recommended to prioritize the evaluation of glucose hypometabolism areas over [18F]FDG uptake values. • The degree of glucose hypometabolism in the epileptogenic focus was not associated with the surgical outcomes of MTLE.

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-ß is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Long-term ANT-DBS effects in pilocarpine-induced epileptic rats: A combined 9.4T MRI and histological study.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) appears to be effective against seizures in animals and humans however, its therapeutic mechanisms remain elusive. This study aimed to combine 9.4T multimodal magnetic resonance imaging (MRI) with histology to investigate the longitudinal effects of long-term ANT-DBS in pilocarpine-induced epileptic rats. Status epilepsy (SE) was induced by LiCl-pilocarpine injection in 11 adult male Sprague-Dawley rats. Four weeks after SE, chronic epileptic rats underwent either ANT-DBS (n = 6) or sham-DBS (n = 5) surgery. Electroencephalography (EEG) and spontaneous recurrent seizures (SRS) were recorded for 1 week. The T2-weighted image and images from resting-state functional MRI (rs-fMRI) were acquired at three states: before SE, at 4 weeks post-SE, and at 5 weeks post-DBS. Volumes of the hippocampal subregions and hippocampal-related functional connectivity (FC) were compared longitudinally. Finally, antibodies against neuronal nuclei (NeuN) and glial fibrillary acidic proteins were used to evaluate neuronal loss and astrogliosis in the hippocampus. Long-term ANT-DBS significantly reduced seizure generalization in pilocarpine-induced epileptic rats. By analyzing the gray matter volume using T2-weighted images, long-term ANT-DBS displayed morphometric restoration of the hippocampal subregions. Neuronal protection of the hippocampal subregions and inhibition of astrogliosis in the hippocampal subregions were observed in the ANT-DBS group. ANT-DBS caused reversible regulation of FC in the insula-hippocampus and subthalamic nucleus-hippocampus. Long-term ANT-DBS provides comprehensive protection of hippocampal histology, hippocampal morphometrics, and hippocampal-related functional networks.

Neuroimaging measures of iron and gliosis explain memory performance in aging.

Evidence from animal and histological studies has indicated that accumulation of iron in the brain results in reactive gliosis that contributes to cognitive deficits. The current study extends these findings to human cognitive aging and suggests that magnetic resonance imaging (MRI) techniques like quantitative relaxometry can be used to study iron and its effects in vivo. The effects of iron on microstructure and memory performance were examined using a combination of quantitative relaxometry and multicompartment diffusion imaging in 35 young (21.06 ± 2.18 years) and 28 older (72.58 ± 6.47 years) adults, who also completed a memory task. Replicating past work, results revealed age-related increases in iron content (R2*) and diffusion, and decreases in memory performance. Independent of age group, iron content was significantly related to restricted (intracellular) diffusion in regions with low-moderate iron (hippocampus, caudate) and to all diffusion metrics in regions with moderate-high iron (putamen, globus pallidus). This pattern is consistent with different stages of iron-related gliosis, ranging from astrogliosis that may influence intracellular diffusion to microglial proliferation and increased vascular permeability that may influence all sources of diffusion. Further, hippocampal restricted diffusion was significantly related to memory performance, with a third of this effect related to iron content; consistent with the hypothesis that higher iron-related astrogliosis in the hippocampus is associated with poorer memory performance. These results demonstrate the sensitivity of MRI to iron-related gliosis and extend our understanding of its impact on cognition by showing that this relationship also explains individual differences in memory performance.

Contribution of TSPO imaging in the understanding of the state of gliosis in substance use disorders.

PURPOSE: Recent research in last years in substance use disorders (SUD) synthesized a proinflammatory hypothesis of SUD based on reported pieces of evidence of non-neuronal central immune signalling pathways modulated by drug of abuse and that contribute to their pharmacodynamic actions. Positron emission tomography has been shown to be a precious imaging technique to study in vivo neurochemical processes involved in SUD and to highlight the central immune signalling actions of drugs of abuse. METHODS: In this review, we investigate the contribution of the central immune system, with a particular focus on translocator protein 18 kDa (TSPO) imaging, associated with a series of drugs involved in substance use disorders (SUD) specifically alcohol, opioids, tobacco, methamphetamine, cocaine, and cannabis. RESULTS: The large majority of preclinical and clinical studies presented in this review converges towards SUD modulation of the neuroimmune responses and TSPO expression and speculated a pivotal positioning in the pathogenesis of SUD. However, some contradictions concerning the same drug or between preclinical and clinical studies make it difficult to draw a clear picture about the significance of glial state in SUD. DISCUSSION: Significant disparities in clinical and biological characteristics are present between investigated populations among studies. Heterogeneity in genetic factors and other clinical co-morbidities, difficult to be reproduced in animal models, may affect findings. On the other hand, technical aspects including study designs, radioligand limitations, or PET imaging quantification methods could impact the study results and should be considered to explain discrepancies in outcomes. CONCLUSION: The supposed neuroimmune component of SUD provides new therapeutic approaches in the prediction and treatment of SUD pointing to the central immune signalling.

Analysis of reactive astrogliosis in mouse brain using in situ hybridization combined with immunohistochemistry.

Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries. Here, we present a revised in situ hybridization and immunohistochemistry (IHC) protocol to label the reactive astrocytes in the mouse brain. Several approaches for quantifying astrocyte reactivity lacked sensitivity to discriminate across the spectrum. We optimized in situ hybridization followed by IHC. We provide a staining protocol for quantitative measures of astrocyte reactivity as an independent confirmation of the magnitude of reactive gliosis. For complete details on the use and execution of this protocol, please refer to Muraleedharan et al. (2020).

Diverse Signaling by TGFß Isoforms in Response to Focal Injury is Associated with Either Retinal Regeneration or Reactive Gliosis.

Müller cells may have stem cell-like capability as they regenerate photoreceptor loss upon injury in some vertebrates, but not in mammals. Indeed, mammalian Müller cells undergo major cellular and molecular changes summarized as reactive gliosis. Transforming growth factor beta (TGFß) isoforms are multifunctional cytokines that play a central role, both in wound healing and in tissue repair. Here, we studied the role of TGFß isoforms and their signaling pathways in response to injury induction during tissue regeneration in zebrafish and scar formation in mouse. Our transcriptome analysis showed a different activation of canonical and non-canonical signaling pathways and how they shaped the injury response. In particular, TGFß3 promotes retinal regeneration via Smad-dependent canonical pathway upon regulation of junb gene family and mycb in zebrafish Müller cells. However, in mice, TGFß1 and TGFß2 evoke the p38MAPK signaling pathway. The activation of this non-canonical pathway leads to retinal gliosis. Thus, the regenerative versus reparative effect of the TGFß pathway observed may rely on the activation of different signaling cascades. This provides one explanation of the different injury response in zebrafish and mouse retina.

Failed Hemispherotomy: Insights from Our Early Experience in 40 Patients.

OBJECTIVE: To study the factors responsible for failure of hemispherotomy and outcomes of revision surgery. The effect of the surgeon's learning curve on failures was also analyzed. METHODS: Forty consecutive patients, who underwent functional hemispherotomy through a 4-year period, from the inception of the single-surgeon epilepsy surgery program, were analyzed. RESULTS: A total of 47 functional hemispherotomies were performed in the study period in 40 patients (7 revision surgeries on 6 patients). Mean age of the cohort was 9.45 ± 14.84 years and it included 7 infants (<2 years). Of the 9 patients (23.5%) who failed the first procedure, 6 qualified for revision surgery, all of whom belonged to the cohort of the first 15 patients treated during the first 2 years of the program. Hemimegalencephaly was the most common disease (n = 4). Ipsilateral temporal stem (n = 3), frontobasal connections (n = 2), splenium of corpus callosum (n = 2), and posterior insula (n = 2) were residual undisconnected substrates identified for revision on imaging. The substrates for failure were obvious in 5/6 patients and resulted from incomplete disconnection, implying surgical inadequacy. At the mean follow-up of 30 ± 13.17 months (range, 13-55 months), 35 of 40 patients (87.5%) remained seizure free (Engel class Ia), including 4/6 patients who underwent redo surgery. Revision did not benefit the remaining 2 patients (Engel class III). There was no mortality. CONCLUSIONS: Surgical revision is more common in hemimegalencephaly and in the early days of a surgical program. Affirmative neuroimaging improves the outcomes of subsequent revision surgery.

Dual pathology in a patient with temporal lobe epilepsy associated with neocortical glial scar after brain abscess and end folium sclerosis/hippocampal sclerosis type 3.

End folium sclerosis or hippocampal sclerosis (HS) type 3 is often associated with another coexisting epileptogenic lesion (dual pathology); however, the pathogenesis of HS type 3 remains elusive. A 46-year-old man presented with medically intractable focal aware seizures and focal impaired awareness seizures (FIAS) with occasional focal to bilateral tonic-clonic seizures (FBTCS) two years after surgical treatment with extensive cranial reconstruction for a brain abscess in the right temporal lobe associated with intracranial extension of ipsilateral cholesteatoma. Head magnetic resonance imaging (MRI) at age 49 revealed atrophy of the right cerebral hemisphere including the hippocampus and amygdala. The patient's first epilepsy surgery was a lateral temporal lobectomy, in which the mesial temporal structures were preserved because no epileptiform discharge was detected on the intraoperative electrocorticogram. However, FIAS with FBTCS started 15 months after the operation. The second surgery, amygdalohippocampectomy, at age 52, resulted in the patient being seizure-free again for one year before seizures of the right lateral temporal origin recurred. He underwent a third surgery, resection of the Heschl's and supramarginal gyri, at age 53, but he continued to have drug-resistant epilepsy over two years after that. Histopathological examination revealed dual pathology consisting of glial scar in the lateral temporal lobe and ipsilateral HS type 3 with an unusually severe lesion in the subiculum. No significant inflammatory change was observed. The clinicopathological features in the present case indicate that HS developed secondarily in the context of neocortical epilepsy due to glial scar, suggesting a role of repetitive abnormal electrical input from neocortical epileptogenic lesions into the hippocampus finally via the perforant pathway in the pathogenesis of HS type 3. Severe hippocampal atrophy on preoperative MRI together with its silent electrocorticogram recording at initial epilepsy surgery may represent clinically pre-epileptogenic HS in a seizure-free "silent or latent period" before completion of hippocampal epileptogenesis to the extent that clinical epileptic seizures occur.

Prevalence of MRI abnormalities in people with epilepsy in rural China.

OBJECTIVE: To assess the prevalence of brain MRI abnormalities in people with epilepsy in rural China and to compare it with that of individuals in the United Kingdom. METHODS: Brain MRI scans were obtained in people with epilepsy who participated in a rural community-based program in China between July 2010 and December 2012. Individual epileptogenic lesion types were reviewed and their associations with seizure control examined. The MRI findings were compared with 2 previous similar studies in the United Kingdom. RESULTS: Among the 597 individuals (58% male, median age 38 years) with MRI scans analyzed, 488 (82%) had active epilepsy. The MRI was abnormal in 389 individuals (65%), with potentially epileptogenic lesion in 224 (38%) and nonspecific abnormalities in 165 (28%), and 108 (18%) were potentially resectable. The potentially epileptogenic lesions were less frequently detected in children (<18 years old, 12 of 68, 18%) than in adults (212 of 529, 40%; p < 0.001). In people with potentially epileptogenic lesions, 67% (150 of 224) had failed ≥2 antiseizure medications. They had higher risk of uncontrolled epilepsy than those with normal MRI (risk ratio [RR] 1.25; p < 0.001) and those with nonspecific abnormality (RR 1.15; p = 0.002) after adjustment for age and sex. The diagnostic yield of MRI was similar to that reported in community- and hospital-based studies in the United Kingdom. CONCLUSIONS: More than one-third of people with chronic epilepsy in rural China have potentially epileptogenic lesions identifiable on brain MRI, with two-thirds fulfilling the definition of pharmacoresistance. These findings highlight the magnitude of the unmet needs for epilepsy surgery in China.

Posterior quadrant disconnection for sub-hemispheric drug refractory epilepsy.

The posterior quadratic epilepsy (PQE) is a form of a multilobar epilepsy, involving the temporal-parietal and occipital lobes. Basically, epilepsies with localized networks to the posterior temporal, posterior parietal, and occipital lobes can benefit from this type of surgery. Gliosis due to perinatal insult and cortical dysplasis and angiomas in Sturge Weber syndrome involving the PQ have often been cited in the literature as the etiology for PQE. However, before considering surgery, it is important to localize the epileptogenic focus through a complete pre operative work up involving; EEG (Electro-Encephalo-Graphy), video EEG, single photon emission computed tomography (SPECT), positron emission tomography (PET), and magneto encephalography (MEG). Historically, these pathologies were dealt with multi-lobar resections, which were associated with high morbidity and mortality, owing to blood loss, especially in young children, hydrocephalus, and hemosiderosis. Based on the theory of networks involved in epileptogenesis, the concept of disconnection in epilepsy surgery was introduced. Delalande and colleagues, described the technique of hemispheric disconnection (functional hemispherectomy) for pathologies like: hemimegalencephaly, rasmussens encephalitis involving the entire hemisphere. The technique has evolved with time, moving towards minimally invasive endoscopic vertical hemispherotomy, described by Chandra and colleagues.[1],[2] The posterior quadrant disconnection (PQD) evolved as a tailored disconnection on similar lines as hemispherotomy, for managing refractory epilepsy arising from the posterior quadrant.[3] The technique and principles involved in the PQD surgery are similar to the those of peri-insular hemispherotomy and has been described in the literature by few authors.[3],[4],[5],[6] The technique of performing PQD will be described here in a step-wise fashion with illustrations supplemented by a surgical video.

Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis?

Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P = 0.03), with greater choline levels linked with worse pain interference (r = 0.41, P = 0.01). In addition, reduced resting functional connectivity between aIns and putamen was associated with both pain interference (whole brain analysis, pcorrected < 0.01) and elevated aIns choline (r = -0.37, P = 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P < 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r = 0.49, P = 0.03). Choline, a putative neuroinflammatory H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.

Radiologic evidence that hypothalamic gliosis is improved after bariatric surgery in obese women with type 2 diabetes.

BACKGROUND/OBJECTIVES: Hypothalamic neurons play a major role in the control of body mass. Obese subjects present radiologic signs of gliosis in the hypothalamus, which may reflect the damage or loss of neurons involved in whole-body energy homeostasis. It is currently unknown if hypothalamic gliosis (1) differs between obese nondiabetic (ND) and obese diabetic subjects (T2D) or (2) is modified by extensive body mass reduction via Roux-n-Y gastric bypass (RYGB). SUBJECTS/METHODS: Fifty-five subjects (all female) including lean controls (CT; n = 13), ND (n = 28), and T2D (n = 14) completed at least one study visit. Subjects underwent anthropometrics and a multi-echo MRI sequence to measure mean bilateral T2 relaxation time in the mediobasal hypothalamus (MBH) and two reference regions (amygdala and putamen). The obese groups underwent RYGB and were re-evaluated 9 months later. Analyses were by linear mixed models. RESULTS: Analyses of T2 relaxation time at baseline showed a group by region interaction only in the MBH (P < 0.0001). T2D had longer T2 relaxation times compared to either CT or ND groups. To examine the effects of RYGB on hypothalamic gliosis a three-way (group by region by time) mixed effects model adjusted for age was executed. Group by region (P < 0.0001) and region by time (P = 0.0005) interactions were significant. There was a reduction in MBH relaxation time by RYGB, and, although the T2D group still had higher T2 relaxation time overall compared to the ND group, the T2D group had significantly lower T2 relaxation time after surgery and the ND group showed a trend. The degree of reduction in MBH T2 relaxation time by RYGB was unrelated to clinical outcomes. CONCLUSION: T2 relaxation times, a marker of hypothalamic gliosis, are higher in obese women with T2D and are reduced by RYGB-induced weight loss.

Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention.

How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.

3D-Double-Inversion recovery detects perilesional gliosis better than 3D-FLAIR and postcontrast T1 imaging in calcified neurocysticercosis.

BACKGROUND: Perilesional gliosis is an important substrate for seizures in patients harboring a calcified neurocysticercosis (NCC) lesion and magnetic resonance imaging (MRI) is useful for evaluating gliosis. AIMS: The purpose of this study was to evaluate the usefulness of double-inversion recovery (DIR) sequence for identifying perilesional gliosis. SETTINGS AND DESIGN: Hospital-based cross-sectional study. METHODS AND MATERIALS: Forty-five patients with seizures were included in this study and a total of 88 calcified lesions identified on susceptibility weighted imaging (SWI) were evaluated on 3D-fluid attenuating inversion recovery (FLAIR), 3D-DIR, and 3D-postcontrast T1-weighted imaging on a 3T MRI for the presence of perilesional signal changes/enhancement. Perilesional signal was rated on a semiquantitative scale from grade 0 to 2 by independent raters. STATISTICAL ANALYSIS USED: Friedman, Wilcoxon signed rank, and Kappa tests were used. RESULTS: 3D-DIR sequence performed better than both 3D-FLAIR and postcontrast 3D-T1W sequences as more number of lesions showed perilesional signal change on DIR sequence. DIR sequence showed perilesional signal abnormality in 24 lesions in which 3D-FLAIR was normal, whereas in another 18 lesions, it demonstrated perilesional signal changes better than 3D-FLAIR. In only three lesions, FLAIR was found to be superior to DIR sequence, whereas postcontrast T1W images showed rim enhancement in five cases where no perilesional signal change was seen on FLAIR/DIR sequences. CONCLUSIONS: Combining 3D-DIR with 3D-FLAIR, and postcontrast 3D-T1W sequences is beneficial for evaluation of calcified NCC lesions and 3D-DIR sequence is better than other two sequences for perilesional signal abnormalities.

Treatment-Related Uptake of O-(2-18F-Fluoroethyl)-l-Tyrosine and l-[Methyl-3H]-Methionine After Tumor Resection in Rat Glioma Models.

Assessment of residual tumor after resection of cerebral gliomas can be difficult with MRI and may be improved by amino acid PET. The aim of this experimental study was to investigate uptake of 2-18F-fluoroethyl-l-tyrosine (18F-FET) and l-[methyl-3H]-methionine (3H-MET) in residual tumor after surgery and possible false-positive uptake in treatment-related changes. Methods: F98 or GS-9L rat gliomas were implanted into the brain of 64 rats. Tumors were resected after 1 wk of tumor growth, and sham surgery was performed in an additional 10 animals. At different time points after surgery (1, 2, 3, 7, and 14-16 d), rats underwent ex vivo dual-tracer autoradiography using 18F-FET and 3H-MET. Histologic slices were evaluated by immunostaining for cell density and astrogliosis. Tracer uptake was quantified by lesion-to-brain ratios (L/B) at the rim of the resection cavity (considered treatment-related uptake) and in residual or recurrent tumor tissue. Four animals showing no residual tumor underwent PET 3 d after surgery to examine time-activity curves of 18F-FET uptake in treatment-related changes. Results: Treatment-related uptake with a mean L/B of 2.0 ± 0.3 for 18F-FET and a mean L/B of 1.7 ± 0.2 for 3H-MET was noted at the rim of the resection cavity in the first week after surgery, decreasing significantly by 14-16 d (P < 0.01). Treatment-related tracer uptake was significantly higher for 18F-FET than for 3H-MET (P < 0.001). Tracer uptake in rat gliomas exceeded treatment-related tracer uptake at all time points (P < 0.001), but the latter was in the range of human gliomas. Reactive astrogliosis was noted near the resection cavity from the second day after surgery. Time-activity curves of 18F-FET uptake in those areas revealed constantly increasing uptake. Conclusion: Surgery may induce significant treatment-related 18F-FET and 3H-MET uptake near the resection cavity in the first week after surgery, presumably caused by reactive astrogliosis. Treatment-related tracer uptake was less pronounced for 3H-MET, indicating that 11C-MET may be better suited for assessing the postoperative situation than 18F-FET. Assessment of residual tumor after surgery by amino acid PET seems to be more reliable after an interval of 14 d.

Neuroradiological findings in patients with "non-lesional" focal epilepsy revealed by research protocol.

AIM: To evaluate whether a dedicated epilepsy research protocol with expert image re-evaluation can increase identification of patients with lesions and to attempt to ascertain the potential reasons why lesions were not identified previously on earlier clinical magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty-three patients (26 female) with focal refractory epilepsy who had failed at least two trials of anti-epileptic drug treatments were studied. Patients were recruited prospectively into the study if previous clinical MRI was deemed to be "non-lesional" by the clinicians involved in the initial assessment. Three-dimensional (3D) T1-weighted (T1W), T2-weighted (T2W), T2 fluid-attenuated inversion recovery (T2-FLAIR) sequences, and two-dimensional (2D) coronal T1-/T2W FLAIR were assessed by a neuroradiologist, including the previous clinical MRI of individual patients. RESULTS: Twenty-nine or 43 (67%) patients remained MRI-negative after scanning with the epilepsy-dedicated protocol and image reappraisal by expert consultant neuroradiologists; however, 14/43 (33%) patients were found to have potentially epileptogenic brain lesions. The lesion that most frequently escaped the attention of clinicians was hippocampal sclerosis (nine cases, of which two had an additional focal cortical dysplasia, FCD), followed by single FCDs (two cases), and others including gliosis, encephalocoele, and amygdala enlargement (one case each). Eleven of the 14 (79%) previously "non-lesional" patients had electroencephalogram (EEG) imaging-concordant localisation features, rendering them potential candidates for resective surgery. CONCLUSIONS: The primary factors explaining the newly identified lesions were the choice of MRI sequences, imaging parameters, data quality, lesion not reported (human factor), and loss of information through incomplete documentation. It is important for all clinicians to proceed meticulously in the detailed assessment of epilepsy-dedicated in-vivo MRI and discuss difficult patient cases in multidisciplinary team meetings.

Efficacy of STA-MCA bypass surgery in moyamoya angiopathy: long-term follow-up of the Caucasian Krupp Hospital cohort with 81 procedures.

BACKGROUND: Despite the consensus on the efficacy of revascularizing surgery in moyamoya angiopathy (MA) in Asia, the indication in Caucasian moyamoya patients is controversially discussed. OBJECTIVE: The efficacy of revascularizing surgery in adult European patients with MA should be clarified. METHODS: This study retrospectively analyzed the rate of further strokes and hemorrhages as well as MRI and Duplex ultrasound features during long-term follow up after STA-MCA bypass. RESULTS: Eighty-one STA-MCA bypass procedures in 54 patients with MA operated in one single German institution were analyzed. All 54 patients (100%) were Caucasians. After two diffusion restricted spots in MRI perioperatively (2.5%) and short-lasting symptoms directly after surgery, no patient experienced further new symptoms related to stroke or hemorrhages nor no new gliotic scars or microbleeds on MRI for 38.2 months. Duplex ultrasound 3 months after surgery documented bypass patency in 100% and sonographic sign for good relevance of the bypass in 96.2%. In addition, the diameter of the donor vessel had increased in 89.9% as an indicator for the relevance of the bypass. Semi-quantitative analysis of perfusion changes in the operated hemispheres demonstrated an increase in perfusion in the MCA territory in 56 of 74 (75.7%) hemispheres 36.7 months after surgery. In MRA images, a reduction of typical moyamoya collaterals was found in 65 of 79 hemispheres (82.3%) after a mean of 37.2 months. CONCLUSION: Direct STA-MCA bypass is an effective therapy in Caucasian patients with hemodynamically compromised MA.

Evaluation of the Safety and Efficacy of the Therapeutic Potential of Adipose-Derived Stem Cells Injected in the Cerebral Ischemic Penumbra.

INTRODUCTION: Stroke represents an attractive target for cell therapy. Although different types of cells have been employed in animal models with variable results, the human adipose-derived stem cells (hASCs) have demonstrated favorable characteristics in the treatment of diseases with inflammatory substrate, but experience in their intracerebral administration is lacking. The purpose of this study is to evaluate the effect and safety of the intracerebral application of hASCs in a stroke model. METHODS: A first group of Athymic Nude mice after stroke received a stereotactic injection of hASCs at a concentration of 4 × 104/µL at the penumbra area, a second group without stroke received the same cell concentration, and a third group had only stroke and no cells. After 7, 15, and 30 days, the animals underwent fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging; subsequently, they were sacrificed for histological evaluation (HuNu, GFAP, IBA-1, Ki67, DCX) of the penumbra area and ipsilateral subventricular zone (iSVZ). RESULTS: The in vitro studies found no alterations in the molecular karyotype, clonogenic capacity, and expression of 62 kDa transcription factor and telomerase. Animals implanted with cells showed no adverse events. The implanted cells showed no evidence of proliferation or differentiation. However, there was an increase of capillaries, less astrocytes and microglia, and increased bromodeoxyuridine and doublecortin-positive cells in the iSVZ and in the vicinity of ischemic injury. CONCLUSIONS: These results suggest that hASCs in the implanted dose modulate inflammation, promote endogenous neurogenesis, and do not proliferate or migrate in the brain. These data confirm the safety of cell therapy with hASCs.