Detection of ischemic neuronal damage with [(18) F]BMS-747158-02, a mitochondrial complex-1 positron emission tomography ligand: Small animal PET study in rat brain

The acute and subacute ischemic neuronal damage in rat brain caused by photochemically induced thrombosis (PIT) was imaged using [¹⁸F]BMS‐747158‐02 ([¹⁸F]BMS) for mitochondrial complex‐1 (MC‐1) and [¹¹C](R)‐PK11195 ([¹¹C](R)‐PK) for peripheral benzodiazepine receptor [PBR; translocator protein] at preischemic “Normal,” 1 (day 1), and 7 days (day 7) after ischemic insult. When [¹⁸F]BMS was intravenously injected into “Normal” rat, it was rapidly taken up into the brain, in which it showed a homogeneous distribution, and the uptake was suppressed by rotenone, a specific MC‐1 inhibitor. The specificity of [¹⁸F]BMS binding to MC‐1 was also confirmed by living brain slice imaging. At day 1, [¹⁸F]BMS uptake was low in infarct and peri‐infarct regions where neuronal damage was detected by 2,3,5‐triphenyltetrazolium chloride (TTC) staining. At day 7, the damaged areas determined using [¹⁸F]BMS revealed some discrepancy from those detected by TTC staining, suggesting that TTC stained not only surviving cells but also activated microglial cells in the peri‐infarct region. This was also confirmed by [¹¹C](R)‐PK imaging and immunohistochemical assessment with Iba1 antibody. In contrast, the uptake pattern of [¹⁸F]BMS was consistent with immunohistochemical assessment with NeuN antibody at both days 1 and 7. These results demonstrated that [¹⁸F]BMS could be a promising positron emission tomography ligand to assess the neuronal damage induced by ischemic insult in both acute and subacute phases. Synapse 2012. © 2012 Wiley Periodicals, Inc.     

Juvenile Psammomatoid Ossifying Fibroma with Visual Disturbance: A Case Report with Imaging Features

Juvenile psammomatoid ossifying fibroma (JPOF) of the sphenoid sinus is a rare subtype of ossifying fibroma of the sinonasal cavity and facial bone in young adults. Computed tomographic (CT) and magnetic resonance (MR) imaging features of JPOF have been reported, but to our knowledge, positron emission tomography (PET) findings have not been described. We present a 19‐year‐old woman with right visual disturbance whom we diagnosed with JPOF and describe imaging findings in her case. CT revealed a well‐circumscribed fibro‐osseous mass surrounding the right optic canal, with expansile, mixed soft tissue and thick bone density. MR imaging showed low signal intensity in the mass on both T₁‐ and T₂‐weighted images. [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and [¹¹C]methyl‐L‐methionine ([¹¹C]Met) PET/CT showed abnormal uptake in the lesion, with standardized uptake values (SUV) of 6.2 ([¹⁸F]FDG) and 4.6 ([¹¹C]Met). Familiarity with the imaging features of this rare disease aids its differentiation from other more familiar lesions to permit appropriately aggressive therapy and improve prognosis.     

Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study

[11C](R)PK11195-PET is a marker of activated microglia while [11C]PIB-PET detects raised amyloid load. Here we studied in vivo the distributions of amyloid load and microglial activation in Alzheimer's disease (AD) and their relationship with cognitive status. Thirteen AD subjects had [11C](R)PK11195-PET and [11C]PIB-PET scans. Ten healthy controls had [11C](R)PK11195-PET and 14 controls had [11C]PIB-PET scans. Region-of-interest analysis of [11C](R)PK11195-PET detected significant 20–35% increases in microglial activation in frontal, temporal, parietal, occipital and cingulate cortices (p < 0.05) of the AD subjects. [11C]PIB-PET revealed significant two-fold increases in amyloid load in these same cortical areas (p < 0.0001) and SPM (statistical parametric mapping) analysis confirmed the localisation of these increases to association areas. MMSE scores in AD subjects correlated with levels of cortical microglial activation but not with amyloid load. The inverse correlation between MMSE and microglial activation is compatible with a role of microglia in neuronal damage.     

Imaging of δ- and μ-opioid receptors in temporal lobe epilepsy by positron emission tomography

The involvement of opioid neurotransmitter systems in seizure mechanisms is well documented. In previous positron emission tomography (PET) studies in patients with unilateral temporal lobe epilepsy, we have found evidence for differential regulation of the opioid-receptor subtypes. The present study extends our previous observations to δ-opioid receptors by using the δ-receptor-selective antagonist [¹¹C]methylnatrindole ([¹¹C]MeNTI). Paired measurements of δ- and μ-opioid receptor binding and metabolic activity were performed with PET using [¹¹C]MeNTI and [¹¹C]carfentanil ([¹¹C]CFN) and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), respectively. Binding of [¹¹C]MeNTI and [¹¹C]CFN increased and [¹⁸F]FDG uptake decreased in the temporal cortex (TC) ipsilateral to the focus. Decreases in [¹⁸F]FDG uptake were more widespread regionally than were increases in opioid receptors. Increases in the δ- and μ-receptor binding showed different regional patterns. Increases in δ-receptor binding were confined to the middle aspect of the inferior TC, whereas binding of δ receptors increased in the mid-inferior TC and anterior aspect of the middle and superior TC. The increase in δ receptors suggests their anticonvulsant action, as previously shown for the δ-receptor subtype, whereas the different regional pattern of receptor alterations suggest the distinct roles of different opioid-receptor subtypes in seizure phenomena.     

Comparing α7 nicotinic acetylcholine receptor binding,amyloid‐β deposition,and mitochondria complex‐I function in living brain: A PET study in aged monkeys

This study was aimed to assess the correlations among α7 nicotinic acetylcholine receptor (α7‐nAChR) binding, amyloid‐β (Aβ) deposition, and mitochondrial complex I (MC‐I) activity in the brain of aged monkeys (Macaca mulatta). Positron emission tomography (PET) measurements with [¹¹C](R)‐MeQAA, [¹¹C]PIB, and [¹⁸F]BCPP‐EF were conducted in monkeys in a conscious condition. [¹¹C](R)‐MeQAA binding was analyzed by a simplified reference tissue model to calculate nondisplaceable binding potential (BP_ND), [¹¹C]PIB uptake was calculated by standard uptake value ratio (SUVR), and [¹⁸F]BCPP‐EF binding was determined by Logan graphical analysis to calculate total distribution volume (V_T) with arterial blood sampling. Higher brain uptake was determined in the thalamus, hippocampus, striatum, and cortical regions for [¹¹C](R)‐MeQAA, while being lower in the cerebellum. Significant age‐related reduction of [¹¹C](R)‐MeQAA binding to α7‐nAChR was determined only in the occipital cortex. The plot of Vt of [¹⁸F]BCPP‐EF against BP_ND of [¹¹C](R)‐MeQAA indicated a significant negative correlation in the hippocampus and cortical regions in aged animals. Plotting of SUVR of [¹¹C]PIB against BP_ND of [¹¹C](R)‐MeQAA showed a positive correlation. The in vivo binding of [¹¹C](R)‐MeQAA could reflect the upregulation of α7‐nAChR induced by neurodegenerative damage determined by Aβ deposition as well as impaired MC‐I activity in living brain. Synapse 69:475–483, 2015. © 2015 Wiley Periodicals, Inc.     

Assessing neuronal density in peri‐infarct cortex with PET: Effects of cortical topology and partial volume correction

The peri‐infarct cortex (PIC) is the site of long‐term physiologic changes after ischemic stroke. Traditional methods for delineating the peri‐infarct gray matter (GM) have used a volumetric Euclidean distance metric to define its extent around the infarct. This metric has limitations in the case of cortical stroke, i.e., those where ischemia leads to infarction in the cortical GM, because the vascularization of the cerebral cortex follows the complex, folded topology of the cortical surface. Instead, we used a geodesic distance metric along the cortical surface to subdivide the PIC into equidistant rings emanating from the infarct border and compared this new approach to a Euclidean distance metric definition. This was done in 11 patients with [F‐18]‐Flumazenil ([18‐F]‐FMZ) positron emission tomography (PET) scans at 2 weeks post‐stroke and at 6 month follow‐up. FMZ is a PET radiotracer with specific binding to the alpha subunits of the type A γ‐aminobutyric acid (GABAA) receptor. Additionally, we used partial‐volume correction (PVC) of the PET images to compensate for potential cortical thinning and long‐term neuronal loss in follow‐up images. The difference in non‐displaceable binding potential (BP_ND) between the stroke unaffected and affected hemispheres was 35% larger in the geodesic versus the Euclidean peri‐infarct models in initial PET images and 48% larger in follow‐up PET images. The inter‐hemispheric BP_ND difference was approximately 17–20% larger after PVC when compared to uncorrected PET images. PET studies of peri‐infarct GM in cortical strokes should use a geodesic model and include PVC as a preprocessing step. Hum Brain Mapp 38:326–338, 2017. © 2016 Wiley Periodicals, Inc.     

Impact of molecular imaging on the diagnostic process in a memory clinic

Background[¹¹C]Pittsburgh compound B ([¹¹C]PIB) and [¹⁸F]-2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population.MethodsOne hundred fifty-four patients underwent paired dynamic [¹¹C]PIB and static [¹⁸F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results.Results[¹¹C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer’s disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [¹⁸F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [¹¹C]PIB and [¹⁸F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients.ConclusionsIn a memory clinic setting, combined [¹¹C]PIB and [¹⁸F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low.     

Tau,amyloid, and hypometabolism in a patient with posterior cortical atrophy

Determining the relative contribution of amyloid plaques and neurofibrillary tangles to brain dysfunction in Alzheimer disease is critical for therapeutic approaches, but until recently could only be assessed at autopsy. We report a patient with posterior cortical atrophy (visual variant of Alzheimer disease) who was studied using the novel tau tracer [¹⁸F]AV‐1451 in conjunction with [¹¹C]Pittsburgh compound B (PIB; amyloid) and [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography. Whereas [¹¹C]PIB bound throughout association neocortex, [¹⁸F]AV‐1451 was selectively retained in posterior brain regions that were affected clinically and showed markedly reduced [¹⁸F]FDG uptake. This provides preliminary in vivo evidence that tau is more closely linked to hypometabolism and symptomatology than amyloid. Ann Neurol 2014.     

Comparison of [11C]UCB-J and [18F]FDG PET in Alzheimer’s disease: A tracer kinetic modeling study

[¹¹C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer’s disease (AD). We compared [¹¹C]UCB-J binding for synaptic density and [¹⁸F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K₁ or R₁ for [¹¹C]UCB-J perfusion, V_T (volume of distribution) or DVR to cerebellum for [¹¹C]UCB-J binding to SV2A; and K_i or K_iR to cerebellum for [¹⁸F]FDG metabolism. [¹¹C]UCB-J binding and [¹⁸F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD –compared to CN participants. However, the magnitude of reduction of [¹¹C]UCB-J binding in neocortical regions was less than that observed with [¹⁸F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [¹¹C]UCB-J perfusion showed a similar pattern to [¹⁸F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.     

In vivo imaging of microglial activation by positron emission tomography with [11C]PBR28 in the 5XFAD model of Alzheimer's disease

Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [¹¹C]‐R‐PK11195 has been challenging due to the limitations of the ligand. In this study, it was aimed to evaluate the new TSPO tracer [¹¹C]PBR28 as a marker for microglial activation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired following intravenous administration of [¹¹C]PBR28 in 6‐month‐old 5XFAD mice and in wild‐type controls. Autoradiography with [³H]PBR28 was carried out in the same brains to further confirm the distribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brain sections of the same mice to evaluate the co‐localization of TSPO with microglia. PET imaging revealed that brain uptake of [¹¹C]PBR28 in 5XFAD mice was increased compared with control mice. Moreover, binding of [³H]PBR28, measured by autoradiography, was enriched in cortical and hippocampal brain regions, coinciding with the positive staining of the microglial marker Iba‐1 and amyloid deposits in the same areas. Furthermore, double‐staining using antibodies against TSPO demonstrated co‐localization of TSPO with microglia and not with astrocytes in 5XFAD mice and human post‐mortem AD brains. The data provided support of the suitability of [¹¹C]PBR28 as a tool for in vivo monitoring of microglial activation and assessment of treatment response in future studies using animal models of AD. GLIA 2016;64:993–1006     

In vivo [11C] flumazenil-PET correlates with ex vivo [3H] flumazenil autoradiography in hippocampal sclerosis

By using [¹¹C]flumazenil-positron emission tomography ([¹¹C]FMZ-PET), we have previously shown that reductions of central benzodiazepine receptors (cBZRs) are restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) caused by unilateral hippocampal sclerosis (HS). Receptor autoradiographic studies on resected hippocampal specimens from the same patients demonstrated loss of cBZRs that was over and above loss of neurons in the CA1 subregion. Here, we report the first direct comparison of in vivo cBZR binding with [¹¹C]FMZ-PET and ex vivo binding using [³H]FMZ autoradiography. We applied a magnetic resonance imaging-based method for partial volume effect correction to the PET images of [¹¹C]FMZ volume of distribution ([¹¹C]FMZ V_d) obtained in 10 patients with refractory mTLE due to unilateral, hisologically verifed HS. Saturation autoradiography was performed on the hippocampal specimens obtained from the same patients, allowing calculation of receptor availability ([³H]FMZ B_max). After correction for partial volume effect, [¹¹C]FMZ V_d in the body of epileptogenic hippocampus was reduced by a mean of 42.1% compred with normal controls. [³H]FMZ b_max, determined autoradiographically from the same hippocampal tissue, was reduced by a mean of 42.7% compared with control hippocampi. Absolute in vivo and ex vivo measurements of cBZR binding for the body of the hippocampus were significantly correlated in each individual. Our study demonstrates that reduction of available cBZR on remaining neuron in HS can be reliably detected in vivo by using [¹¹C]FMZ-PET after correction for partial volume effect.     

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11C]UCB-J and [18F]FDG PET Study

Background

Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor.

Objective

The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease.

Method

Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) PET and [¹¹C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level.

Results

We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density.

Conclusion

Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [¹⁸F]FDG PET and [¹¹C]UCB-J PET in Lewy body patients. The magnitude of reduced [¹⁸F]FDG uptake was greater than the corresponding decline in [¹¹C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

In vivo synaptic density relates to glucose metabolism at rest in healthy subjects,but is strongly modulated by regional differences

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [¹¹C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [¹⁸F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [¹¹C]UCB-J were indeed highly significantly correlated (r > 0.47, p < 0.001). However, regional differences in relative [¹⁸F]FDG and [¹¹C]UCB-J uptake were observed, with up to 19% higher [¹¹C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.     

In vivo evaluation of N‐[18F]fluoroethylpiperidin‐4ylmethyl acetate in rats compared with MP4A as a probe for measuring cerebral acetylcholinesterase activity

[¹¹C]MP4A is an established radioprobe for quantification of cerebral acetylcholinesterase (AChE) activity by positron emission tomography (PET) based on the kinetics of AChE‐mediated metabolism and metabolite trapping. It has been used to assess the deficiency in cholinergic innervation in the brain of patients with dementia. Because ¹⁸F has a longer half‐life than ¹¹C, ¹⁸F‐labeled derivatives of [¹¹C]MP4A allow delivery of the probe to other PET centers, making AChE measurement more widely applicable. Previously, N‐[¹⁸F]fluoroethylpiperidin‐4ylmethyl acetate ([¹⁸F]FEP‐4MA) showed that the ¹⁸F‐labeled analog of MP4A possessed desirable properties for the quantification of cerebral AChE activity by PET. Here, we evaluated the in vivo kinetics of [¹⁸F]FEP‐4MA and validated the responsiveness of brain uptake to AChE activity based on a mathematical model derived from the AChE‐mediated trapping rationale and compared it with MP4A in rats. Almost all radioactivity in the brain was composed of [¹⁸F]FEP‐4MA and the hydrolyzed metabolite at 0–60‐min postinjection. When the authentic radioprobe was not observed in the brain, the regional ¹⁸F uptake in the brain correlated well with regional MP4A uptake, and the elimination rate of ¹⁸F from the brain was higher than that of the metabolite of MP4A. The responsiveness of regional ¹⁸F uptake in the brain was examined by simultaneous assay of ¹⁸F concentration, relative blood flow, and AChE activity. Regional ¹⁸F uptake correlated with regional AChE activity as well as that of MP4A. Therefore, we concluded that [¹⁸F]FEP‐4MA would be applicable to clinical PET study for quantifying cerebral AChE activity. Synapse 64:209–215, 2010. © 2009 Wiley‐Liss, Inc.     

Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex

OBJECTIVE: Using interictal alpha-[11C]methyl-l-tryptophan ([11C]AMT) PET scan, the authors have undertaken a quantitative analysis of all tubers visible on MRI or 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET, to determine the relationship between [11C]AMT uptake and epileptic activity on EEG. BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, often associated with cortical tubers and intractable epilepsy. The authors have shown previously that [11C]AMT PET scans show high tracer uptake in some epileptogenic tubers and low uptake in the remaining tubers. METHODS: Eighteen children, age 7 months to 16 years, were studied. Patients underwent video-EEG monitoring, PET scans of [11C]AMT and [18F]FDG, and T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI. [11C]AMT uptake values were measured in 258 cortical tubers delineated with coregistered MRI or [18F]FDG scans. Uptake ratios were calculated between the [11C]AMT uptake in tubers and those for normal cortex (tuber/normal cortex). Using the region of epileptiform activity, the authors performed receiver operator characteristics (ROC) analysis and determined the optimal uptake ratio for detecting presumed epileptogenic tubers. RESULTS: Tuber uptake ratios ranged from 0.6 to 2.0. Tuber uptake ratios in the epileptic lobes were higher than those in the nonepileptic lobes (p < 0.0001). All 15 patients with focal seizure activity showed one or more lesions with uptake ratio above 0.98 in the epileptic lobe. ROC analysis showed that a tuber uptake ratio of 0.98 resulted in a specificity of 0.91. CONCLUSIONS: Cortical tubers with [11C]AMT uptake greater than or equal to normal cortex are significantly related to epileptiform activity in that lobe. Together, interictal [11C]AMT PET and FLAIR MRI improve the detection of potentially epileptogenic tubers in patients with TSC being evaluated for epilepsy surgery.     

Glucose and methionine uptake and proliferative activity in meningiomas.

Despite similar benign histological appearances, proliferative activity of meningiomas varies tumor to tumor, and even region to region in a tumor. To predict proliferative potential before surgery, we compared regional uptake of 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and L-[methyl-11C]methionine ([11C]MET) with histological indices of tumor proliferative activity in 17 specimens from six patients with meningioma obtained by PET guided stereotactic biopsies. Uptake of [11C]MET, an index of protein synthesis rate, significantly correlated not only with the count of nucleolar organizer regions (NORs), a histological index of protein synthesis, but also with Ki-67 index, a histological index of proliferative activity. On the other hand, [18F]FDG uptake showed no significant correlation with Ki-67 index or clinical malignancy. These results suggest that [11C]MET-PET is a useful tool for predicting tumor proliferative potential in meningiomas.     

Intracranial EEG versus flumazenil and glucose PET in children with extratemporal lobe epilepsy

OBJECTIVE: To compare abnormalities determined in 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET images with intracranial EEG data in patients with extratemporal lobe epilepsy. BACKGROUND: Although PET studies with FDG and FMZ are being used clinically to localize epileptogenic regions in patients with refractory epilepsy, the electrophysiologic significance of the identified PET abnormalities remains poorly understood. METHODS: We studied 10 patients, mostly children (4 boys, 6 girls, aged 2 to 19 years; mean age, 11 years), who underwent FDG and FMZ PET scans, intracranial EEG monitoring, and cortical resection for intractable epilepsy. EEG electrode positions relative to the brain surface were determined from MRI image volumes. Cortical areas of abnormal glucose metabolism or FMZ binding were determined objectively based on asymmetry measures derived from homotopic cortical areas at three asymmetry thresholds. PET data were then coregistered with the MRI and overlaid on the MRI surface. A receiver operating characteristics (ROC) analysis was performed to determine the specificity and sensitivity of PET-defined abnormalities against the gold standard of intracranial EEG data. RESULTS: FMZ PET detected at least part of the seizure onset zone in all subjects, whereas FDG PET failed to detect the seizure onset region in two of 10 patients. The area under the ROC curves was higher for FMZ than FDG PET for both seizure onset (p = 0.01) and frequent interictal spiking (p = 0.04). Both FMZ and FDG PET showed poor performance for detection of rapid seizure spread (area under the ROC curve not significantly different from 0.5). CONCLUSIONS: [11C]flumazenil (FMZ) PET is significantly more sensitive than 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET for the detection of cortical regions of seizure onset and frequent spiking in patients with extratemporal lobe epilepsy, whereas both FDG and FMZ PET show low sensitivity in the detection of cortical areas of rapid seizure spread. The application of PET, in particular FMZ PET, in guiding subdural electrode placement in refractory extratemporal lobe epilepsy will enhance coverage of the epileptogenic zone.     

Glucose and [11C]flumazenil positron emission tomography abnormalities of thalamic nuclei in temporal lobe epilepsy

OBJECTIVES: To analyze interictal patterns of thalamic nuclei glucose metabolism and benzodiazepine receptor binding in patients with medically intractable temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND: Structural and glucose metabolic abnormalities of the thalamus are considered important in the pathophysiology of TLE. The differential involvement of various thalamic nuclei in humans is not known. METHODS: Twelve patients with TLE underwent volumetric MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes also were measured. RESULTS: The DMN showed significantly lower glucose metabolism and FMZ binding on the side of the epileptic focus. The LAT showed bilateral hypermetabolism and increased FMZ binding. There was a significant correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET abnormalities were associated with a significant volume loss of the thalamus ipsilateral to the seizure focus. CONCLUSIONS: Decreased [11C]flumazenil (FMZ) binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and have strong lateralization value for the seizure focus in human temporal lobe epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss, as suggested by volume loss, but also may indicate impaired gamma-aminobutyric acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections with other parts of the limbic system. Increased glucose metabolism and FMZ binding in the lateral thalamus could represent an upregulation of GABA-mediated inhibitory circuits.     

Dynamic changes in glucose metabolism of living rat brain slices induced by hypoxia and neurotoxic chemical-loading revealed by positron autoradiography

Fresh rat brain slices were incubated with 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degrees C, and serial two-dimensional time-resolved images of [18F]FDG uptake were obtained from these specimens on imaging plates. The fractional rate constant (= k3*) of [18F]FDG proportional to the cerebral glucose metabolic rate (CMRglc) was evaluated by applying the Gjedde-Patlak graphical method to the image data. With hypoxia loading (oxygen deprivation) or glucose metabolism inhibitors acting on oxidative phosphorylation, the k3* value increased dramatically suggesting enhanced glycolysis. After relieving hypoxia < or = 10-min, the k3* value returned to the pre-loading level. In contrast, with > or = 20-min hypoxia only partial or no recovery was observed, indicating that irreversible neuronal damage had been induced. However, after loading with tetrodotoxin (TTX), the k3* value also decreased but returned to the pre-loading level even after 70-min TTX-loading, reflecting a transient inhibition of neuronal activity. This technique provides a new means of quantifying dynamic changes in the regional CMRglc in living brain slices in response to various interventions such as hypoxia and neurotoxic chemical-loading as well as determining the viability and prognosis of brain tissues.     

Clinical utility of 11C-flumazenil positron emission tomography in intractable temporal lobe epilepsy

BACKGROUND: 11C-flumazenil (FMZ) positron emission tomography (PET) is a new entrant into the armamentarium for pre-surgical evaluation of patients with intractable temporal lobe epilepsy (TLE). AIMS: To analyze the clinical utility of FMZ PET to detect lesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to magnetic resonance imaging (MRI), 2-Deoxy-2 [18F] fluoro-D-glucose, (18F FDG) PET, electrophysiological findings and semiology of epilepsy in patients with intractable TLE. MATERIALS AND METHODS: Patients underwent a high resolution MRI, prolonged Video-EEG monitoring before 18F FDG and 11C FMZ PET studies. Regional cortical FMZ PET abnormalities were defined on co-registered PET images using an objective method based on definition of areas of abnormal asymmetry (asymmetry index {AI}>10%). SETTINGS AND DESIGN: Prospective. STATISTICAL ANALYSIS: Student's "t" test. RESULTS: Twenty patients (Mean age: 35.2 years [20-51]; M:F=12:8) completed the study. Mean age at seizure onset was 10.3 years (birth-38 years); mean duration, 23.9 years (6-50 years). Concordance with the MRI lesion was seen in 10 patients (nine with hippocampal sclerosis and one with tuberous sclerosis). In the other 10, with either normal or ambiguous MRI findings, FMZ and FDG uptake were abnormal in all, concordant with the electrophysiological localization of the epileptic foci. Remote FMZ PET abnormalities (n=18) were associated with early age of seizure onset (P=0.005) and long duration of epilepsy (P=0.01). CONCLUSIONS: FMZ-binding asymmetry is a sensitive method to detect regions of epileptic foci in patients with intractable TLE.