PET Imaging Of Translocator Protein Research Articles

47. 11C-ER176 Pet Imaging of Translocator Protein (TSPO) Binding in Major Depression: Relationship to Severity of Real-Time Suicidal Ideation and Negative Affect in the Context of Naturalistic Stressors

47. 11C-ER176 Pet Imaging of Translocator Protein (TSPO) Binding in Major Depression: Relationship to Severity of Real-Time Suicidal Ideation and Negative Affect in the Context of Naturalistic Stressors

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH-Wild-Type Glioblastoma.

The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUVmax on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O 6-alkylguanine DNA methyltransferase (MGMT) and telomerase reverse transcriptase (TERT) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUVmax was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUVmax > 2.2) was related to significantly shorter overall survival (OS; 8.3 vs. 17.8 mo, P = 0.037). Besides SUVmax, prognostic factors for OS were age (P = 0.046), MGMT promoter methylation status (P = 0.032), and T2-weighted MRI volume (P = 0.031). In the multivariate survival analysis, SUVmax in TSPO PET remained an independent prognostic factor for OS (P = 0.023), with a hazard ratio of 2.212 (95% CI, 1.115-4.386) for death in cases with a high TSPO PET signal (SUVmax > 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma.

TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies

IntroductionThe 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity. MethodsWe searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I2 statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05. Results156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, PFDR < 0.001, I2 = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer’s disease (SMD = 0.693, PFDR < 0.001, I2 = 64%) and other neurodegenerative disorders (SMD = 0.929, PFDR < 0.001, I2 = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I2 = 67%) were most prominent for Alzheimer’s disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I2 = 71%) was observed for Alzheimer’s disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all PFDR < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; VT-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance). ConclusionThis study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to VT-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.

Assessing organ-level immunoreactivity in a rat model of sepsis using TSPO PET imaging.

There is current need for new approaches to assess/measure organ-level immunoreactivity and ensuing dysfunction in systemic inflammatory response syndrome (SIRS) and sepsis, in order to protect or recover organ function. Using a rat model of systemic sterile inflammatory shock (intravenous LPS administration), we performed PET imaging with a translocator protein (TSPO) tracer, [18F]DPA-714, as a biomarker for reactive immunoreactive changes in the brain and peripheral organs. In vivo dynamic PET/CT scans showed increased [18F]DPA-714 binding in the brain, lungs, liver and bone marrow, 4 hours after LPS injection. Post-LPS mean standard uptake values (SUVmean) at equilibrium were significantly higher in those organs compared to baseline. Changes in spleen [18F]DPA-714 binding were variable but generally decreased after LPS. SUVmean values in all organs, except the spleen, positively correlated with several serum cytokines/chemokines. In vitro measures of TSPO expression and immunofluorescent staining validated the imaging results. Noninvasive molecular imaging with [18F]DPA-714 PET in a rat model of systemic sterile inflammatory shock, along with in vitro measures of TSPO expression, showed brain, liver and lung inflammation, spleen monocytic efflux/lymphocytic activation and suggested increased bone marrow hematopoiesis. TSPO PET imaging can potentially be used to quantify SIRS and sepsis-associated organ-level immunoreactivity and assess the effectiveness of therapeutic and preventative approaches for associated organ failures, in vivo.

Longitudinal [18F]GE-180 PET Imaging Facilitates In Vivo Monitoring of TSPO Expression in the GL261 Glioblastoma Mouse Model.

The 18 kDa translocator protein (TSPO) is increasingly recognized as an interesting target for the imaging of glioblastoma (GBM). Here, we investigated TSPO PET imaging and autoradiography in the frequently used GL261 glioblastoma mouse model and aimed to generate insights into the temporal evolution of TSPO radioligand uptake in glioblastoma in a preclinical setting. We performed a longitudinal [18F]GE-180 PET imaging study from day 4 to 14 post inoculation in the orthotopic syngeneic GL261 GBM mouse model (n = 21 GBM mice, n = 3 sham mice). Contrast-enhanced computed tomography (CT) was performed at the day of the final PET scan (±1 day). [18F]GE-180 autoradiography was performed on day 7, 11 and 14 (ex vivo: n = 13 GBM mice, n = 1 sham mouse; in vitro: n = 21 GBM mice; n = 2 sham mice). Brain sections were also used for hematoxylin and eosin (H&E) staining and TSPO immunohistochemistry. [18F]GE-180 uptake in PET was elevated at the site of inoculation in GBM mice as compared to sham mice at day 11 and later (at day 14, TBRmax +27% compared to sham mice, p = 0.001). In GBM mice, [18F]GE-180 uptake continuously increased over time, e.g., at day 11, mean TBRmax +16% compared to day 4, p = 0.011. [18F]GE-180 uptake as depicted by PET was in all mice co-localized with contrast-enhancement in CT and tissue-based findings. [18F]GE-180 ex vivo and in vitro autoradiography showed highly congruent tracer distribution (r = 0.99, n = 13, p < 0.001). In conclusion, [18F]GE-180 PET imaging facilitates non-invasive in vivo monitoring of TSPO expression in the GL261 GBM mouse model. [18F]GE-180 in vitro autoradiography is a convenient surrogate for ex vivo autoradiography, allowing for straightforward identification of suitable models and scan time-points on previously generated tissue sections.

PET Imaging of Translocator Protein as a Marker of Malaria-Associated Lung Inflammation.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a severe complication of malaria that occurs despite effective antimalarial treatment. Currently, noninvasive imaging procedures such as chest X-rays are used to assess edema in established MA-ARDS, but earlier detection methods are needed to reduce morbidity and mortality. The early stages of MA-ARDS are characterized by the infiltration of leukocytes, in particular monocytes/macrophages; thus, monitoring of immune infiltrates may provide a useful indicator of early pathology. In this study, Plasmodium berghei ANKA-infected C57BL/6 mice, a rodent model of MA-ARDS, were longitudinally imaged using the 18-kDa translocator protein (TSPO) imaging agent [18F]FEPPA as a marker of macrophage accumulation during the development of pathology and in response to combined artesunate and chloroquine diphosphate (ART+CQ) therapy. [18F]FEPPA uptake was compared to blood parasitemia levels and to levels of pulmonary immune cell infiltrates by using flow cytometry. Infected animals showed rapid increases in lung retention of [18F]FEPPA, correlating well with increases in blood parasitemia and pulmonary accumulation of interstitial inflammatory macrophages and major histocompatibility complex class II (MHC-II)-positive alveolar macrophages. Treatment with ART+CQ abrogated this increase in parasitemia and significantly reduced both lung uptake of [18F]FEPPA and levels of macrophage infiltrates. We conclude that retention of [18F]FEPPA in the lungs is well correlated with changes in blood parasitemia and levels of lung-associated macrophages during disease progression and in response to ART+CQ therapy. With further development, TSPO biomarkers may have the potential to accurately assess the early onset of MA-ARDS.

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression.

Imaging of the glioma microenvironment by TSPO PET.

Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein(TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.

In vivo PET imaging of neuroinflammation in Alzheimer's disease.

Increasing evidence suggests that neuroinflammation contributes to the pathophysiology of many neurodegenerative diseases, especially Alzheimer's disease (AD). Molecular imaging by PET may be a useful tool to assess neuroinflammation in vivo, thus helping to decipher the complex role of inflammatory processes in the pathophysiology of neurodegenerative diseases and providing a potential means of monitoring the effect of new therapeutic approaches. For this objective, the main target of PET studies is the 18kDa translocator protein (TSPO), as it is overexpressed by activated microglia. In the present review, we describe the most widely used PET tracers targeting the TSPO, the methodological issues in tracer quantification and summarize the results obtained by TSPO PET imaging in AD, as well as in neurodegenerative disorders associated with AD, in psychiatric disorders and ageing. We also briefly describe alternative PET targets and imaging modalities to study neuroinflammation. Lastly, we question the meaning of PET imaging data in the context of a highly complex and multifaceted role of neuroinflammation in neurodegenerative diseases. This overview leads to the conclusion that PET imaging of neuroinflammation is a promising way of deciphering the enigma of the pathophysiology of AD and of monitoring the effect of new therapies.

296. Correlating Peripheral and Central Markers of Neuroinflammation to PET Imaging of Translocator Protein (TSPO)

296. Correlating Peripheral and Central Markers of Neuroinflammation to PET Imaging of Translocator Protein (TSPO)

Translocator protein ligands based on N-methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development

Modifications to an N-methyl-(quinolin-4-yl)oxypropanamide scaffold were explored to discover leads for developing new radioligands for PET imaging of brain TSPO (translocator protein), a biomarker of neuroinflammation. Whereas contraction of the quinolinyl portion of the scaffold or cyclization of the tertiary amido group abolished high TSPO affinity, insertion of an extra nitrogen atom into the 2-arylquinolinyl portion was effective in retaining sub-nanomolar affinity for rat TSPO, while also decreasing lipophilicity to within the moderate range deemed preferable for a PET radioligand. Replacement of a phenyl group on the amido nitrogen with an isopropyl group was similarly effective. Among others, compound 20 (N-methyl-N-phenyl-2-[2-(pyridin-2-yl)-1,8-naphthyridin-4-yloxy]propanamide) appears especially appealing for PET radioligand development, based on high selectivity and high affinity (Ki = 0.5 nM) for rat TSPO, moderate lipophilicity (logD = 2.48), and demonstrated amenability to labeling with carbon-11.

Concepts for compact and stable pathway design in yeasts

Modifications to an N-methyl-(quinolin-4-yl)oxypropanamide scaffold were explored to discover leads for developing new radioligands for PET imaging of brain TSPO (translocator protein), a biomarker of neuroinflammation. Whereas contraction of the quinolinyl portion of the scaffold or cyclization of the tertiary amido group abolished high TSPO affinity, insertion of an extra nitrogen atom into the 2-arylquinolinyl portion was effective in retaining sub-nanomolar affinity for rat TSPO, while also decreasing lipophilicity to within the moderate range deemed preferable for a PET radioligand. Replacement of a phenyl group on the amido nitrogen with an isopropyl group was similarly effective. Among others, compound 20 (N-methyl-N-phenyl-2-[2-(pyridin-2-yl)-1,8-naphthyridin-4-yloxy]propanamide) appears especially appealing for PET radioligand development, based on high selectivity and high affinity (Ki = 0.5 nM) for rat TSPO, moderate lipophilicity (logD = 2.48), and demonstrated amenability to labeling with carbon-11.

A Novel PET Imaging Probe for the Detection and Monitoring of Translocator Protein 18 kDa Expression in Pathological Disorders.

A new fluorine-substituted ligand, compound 1 (CB251), with a very high affinity (Ki = 0.27 ± 0.09 nM) and selectivity for the 18-kDa translocator protein (TSPO), is presented as an attractive biomarker for the diagnosis of neuroinflammation, neurodegeneration and tumour progression. To test compound 1 as a TSPO PET imaging agent in vivo, 2-(2-(4-(2-[18F]fluoroethoxy)phenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide ([18F]1; [18F]CB251) was synthesized by nucleophilic aliphatic substitution in a single-step radiolabelling procedure with a 11.1 ± 3.5% (n = 14, decay corrected) radiochemical yield and over 99% radiochemical purity. In animal PET imaging studies, [18F]CB251 provided a clearly visible image of the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND 1.83 ± 0.18), in a neuroinflammation rat model based on the unilateral stereotaxic injection of lipopolysaccharide (LPS), comparable to that of [11C]PBR28 (BPND 1.55 ± 0.41). [18F]CB251 showed moderate tumour uptake (1.96 ± 0.11%ID/g at 1 h post injection) in human glioblastoma U87-MG xenografts. These results suggest that [18F]CB251 is a promising TSPO PET imaging agent for neuroinflammation and TSPO-rich cancers.

Increased radioligand binding to translocator protein correlates with worsened clinical severity and atrophy in Alzheimer's disease

We previously demonstrated that radioligand binding to the 18 kDa translocator protein (TSPO), a marker for inflammation, was greater in patients with Alzheimer's disease (AD) than controls and correlated with clinical severity. We sought to determine the relationship between TSPO binding and progression of AD in a longitudinal study. Eleven patients with either AD or mild cognitive impairment and 8 age-matched controls underwent TSPO PET imaging with 11C-PBR28 at baseline and again after median follow up of 2.7 years. MRI, Pittsburgh Compound B (PIB) PET, and cognitive testing were also performed at baseline and follow up. PET images were corrected for partial volume effects. Regional 11C-PBR28 standardized uptake value ratios were determined using cerebellum as pseudo-reference region. PIB distribution volume ratios were determined using Logan graphical method with cerebellar reference. Among patients, there was a significant correlation between increase in 11C-PBR28 binding and a decline in raw scores on Block Design, Trail Making part B, and Boston Naming Test. The strongest of such correlations occurred in prefrontal and parietal cortices (R > 0.68, P < 0.03). Percent change in 11C-PBR28 binding negatively correlated with %change in voxel count in prefrontal, parietal, and temporal cortices (R < -0.52, P < 0.03). Percent change in 11C-PBR28 correlated with %change in PIB binding in occipital cortex only (R = 0.63, P = 0.037). Controls showed no correlation between 11C-PBR28 binding and brain atrophy. Among patients, ApoE4 carriers (n = 7) had greater increase in 11C-PBR28 binding than non-carriers (n = 4) in inferior temporal cortex (P = 0.042, Mann-Whitney U Test). TSPO increases with worsening clinical severity and cortical atrophy in AD. Larger studies are needed to better determine the relationship between TSPO, fibrillary amyloid load, and ApoE genotype. 11C-PBR28 PET has promise for monitoring AD progression.

Divergent pattern of changes in astrocytosis and fibrillar amyloid plaques as measured by PET in autosomal-dominant and sporadic Alzheimer’s disease

Background: We previously demonstrated that radioligand binding to the 18 kDa translocator protein (TSPO), a marker for inflammation, was greater in patients with Alzheimer’s disease (AD) than controls and correlated with clinical severity. We sought to determine the relationship between TSPO binding and progression of AD in a longitudinal study. Methods: Eleven patients with either AD or mild cognitive impairment and 8 age-matched controls underwent TSPO PET imaging with C-PBR28 at baseline and again after median follow up of 2.7 years. MRI, Pittsburgh Compound B (PIB) PET, and cognitive testing were also performed at baseline and follow up. PET images were corrected for partial volume effects. Regional C-PBR28 standardized uptake value ratios were determined using cerebellum as pseudo-reference region. PIB distribution volume ratios were determined using Logan graphical method with cerebellar reference. Results: Among patients, there was a significant correlation between increase in C-PBR28 binding and a decline in raw scores on Block Design, Trail Making part B, and Boston Naming Test. The strongest of such correlations occurred in prefrontal and parietal cortices (R > 0.68, P < 0.03). Percent change in C-PBR28 binding negatively correlated with %change in voxel count in prefrontal, parietal, and temporal cortices (R< -0.52, P< 0.03). Percent change in C-PBR28 correlated with %change in PIB binding in occipital cortex only (R 1⁄4 0.63, P 1⁄4 0.037). Controls showed no correlation between C-PBR28 binding and brain atrophy. Among patients, ApoE4 carriers (n 1⁄4 7) had greater increase in C-PBR28 binding than noncarriers (n1⁄4 4) in inferior temporal cortex (P1⁄4 0.042, Mann-Whitney U Test). Conclusions:TSPO increases with worsening clinical severity and cortical atrophy in AD. Larger studies are needed to better determine the relationship between TSPO, fibrillary amyloid load, and ApoE genotype. C-PBR28 PET has promise for monitoring AD progression.

How to Perform Translocator Protein PET-CT Scanning for Microglial Activation in Schizophrenia Patients.

Introduction Activated microglia express translocator protein (TSPO) on the outer mitochondrial membrane. PET ligands targeting TSPO allow in vivo non-invasive visualization and quantification of neuroinflammation. Whereas inflammation in schizophrenia was previously studied using 11 C-PK11195, 18 F-PBR111 is a novel second-generation tracer, with high specific TSPO binding and longer half-life. Objective To establish a protocol for 18 F-PBR111 TSPO PET in schizophrenia. Methods A pilot study on a Siemens Biograph mCT PET-scanner in healthy controls and schizophrenia patients (n=9). Results Subjects underwent a 90-minute dynamic brain PET-CT, following i.v. bolus injection of 214±13 MBq 18 F-PBR111. An arterial input function was measured using continuous blood sampling (Twilite, Switzerland) with discrete samples for metabolite analysis. The metabolite corrected plasma input function (IPF) was calculated from the whole blood input function, individual plasma to whole blood and parent fraction data as determined by a SEP-PAK procedure. Dynamic PET data were reconstructed and a post-reconstruction motion correction was applied. Regional tissue time activity curves (TACs) were extracted from the PET images for regions of interest determined from individual MRI images. Total volume of distribution (V T ) was then calculated from fitting a reversible two-tissue compartmental model to the measured TACs using the individual IPF. Prior genotyping for TSPO receptor polymorphism (rs6971) allowed to exclude low-affinity binders (estimated 10% of European population). The procedure was well tolerated. Conclusions We established a protocol for 18 F-PBR111 TSPO PET in healthy subjects and schizophrenia patients, thereby providing useful information for others considering 18 F-PBR111 TSPO PET imaging for evaluation of neuroinflammation.

Identifying brain network dysfunctions during epileptogenesis in a model of temporal lobe epilepsy

Event Abstract Back to Event Identifying brain network dysfunctions during epileptogenesis in a model of temporal lobe epilepsy Daniele Bertoglio1, Halima Amhaoul1, Disha Shah2, Ryo Sakai3, Jeroen Verhaeghe4, Leonie Wyffels4, Steven Staelens4, Marleen Verhoye2, Annemie Van Der Linden2, Jan Aerts3 and Stefanie Dedeurwaerdere1* 1 University of Antwerp, Translational Neuroscience, Belgium 2 University of Antwerp,, Bio-Imaging Lab, Belgium 3 KU Leuven, Department of Electrical Engineering, Belgium 4 University of Antwerp, Molecular Imaging Center Antwerp, Belgium Introduction About 65 million people worldwide have epilepsy, of which half of the patients suffer from acquired forms. Post-traumatic epilepsy (PTE) often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult. Although this latent period clearly represents a therapeutic window, we have not been able to stratify patients at risk for developing PTE. The aim of this study is to determine network alterations associated with the process of epileptogenesis by means of translocator protein (TSPO) PET scans, a biomarker of neuroinflammation, in the kainic acid-induced status epilepticus (KASE) model. Methods 18F-PBR111 PET and T2 MRI scans from 8 control and 16 KASE rats acquired 2 weeks after Status Epilepticus (SE) (latent phase) were taken. Stratification between KASE animals without seizures (n=3) and with spontaneous seizures (n=10) was done by means of video-EEG recordings 3 months after SE (chronic phase). The PET ratio (r50′) was derived as previously validated1. In addition, correlation maps and brain networks were obtained from the TSPO PET r50′ data. Results 18F-PBR111 PET binding (r50′) in the individual volume of Interests (VOIs) 2 weeks post-SE was highly increased in KASE compared to control animals. In addition, some VOIs statistically differed between KASE animals with seizures and without. Finally, correlation maps and brain networks between PET brain regions differed between control, KASE without seizures, and KASE with seizures. Conclusions TSPO correlation maps and brain networks based on TSPO PET imaging showed promise for differentiating KASE animals, which developed epilepsy from those who did not and controls. In addition, we are studying more animals to further validate whether these approaches could be useful in identifying network dysfunctions that may lead to development of epilepsy. Keywords: 18F-PBR111, TSPO, Temporal Lobe Epilepsy (TLE), Kainic acid induced status epilepticus (KASE), Brain network analysis Conference: 11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015. Presentation Type: Oral or Poster presentation Topic: Neuroscience Citation: Bertoglio D, Amhaoul H, Shah D, Sakai R, Verhaeghe J, Wyffels L, Staelens S, Verhoye M, Van Der Linden A, Aerts J and Dedeurwaerdere S (2015). Identifying brain network dysfunctions during epileptogenesis in a model of temporal lobe epilepsy. Front. Neurosci. Conference Abstract: 11th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2015.89.00043 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Apr 2015; Published Online: 05 May 2015. * Correspondence: Prof. Stefanie Dedeurwaerdere, University of Antwerp, Translational Neuroscience, Wilrijk, 2610, Belgium, stefanie.dedeurwaerdere@uantwerpen.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Daniele Bertoglio Halima Amhaoul Disha Shah Ryo Sakai Jeroen Verhaeghe Leonie Wyffels Steven Staelens Marleen Verhoye Annemie Van Der Linden Jan Aerts Stefanie Dedeurwaerdere Google Daniele Bertoglio Halima Amhaoul Disha Shah Ryo Sakai Jeroen Verhaeghe Leonie Wyffels Steven Staelens Marleen Verhoye Annemie Van Der Linden Jan Aerts Stefanie Dedeurwaerdere Google Scholar Daniele Bertoglio Halima Amhaoul Disha Shah Ryo Sakai Jeroen Verhaeghe Leonie Wyffels Steven Staelens Marleen Verhoye Annemie Van Der Linden Jan Aerts Stefanie Dedeurwaerdere PubMed Daniele Bertoglio Halima Amhaoul Disha Shah Ryo Sakai Jeroen Verhaeghe Leonie Wyffels Steven Staelens Marleen Verhoye Annemie Van Der Linden Jan Aerts Stefanie Dedeurwaerdere Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients

Imaging the 18-kDa translocator protein (TSPO) is considered a potential tool for in vivo evaluation of microglial activation and neuroinflammation in the early stages of Alzheimer's disease (AD). ((R)-1-(2-chlorophenyl)-N-[(11)C]-methyl-N-(1-methylpropyl)-3-isoquinoline caboxamide ([(11)C]-(R)-PK11195) has been widely used for PET imaging of TSPO and, despite its low specific-to-nondisplaceable binding ratio, increased TSPO binding has been shown in AD patients. The high-affinity radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoroethyl-5-methoxybenzyl)acetamide ([(18)F]FEDAA1106) has been developed as a potential in vivo imaging tool for better quantification of TSPO binding. The aim of this study was to quantify in vivo binding of [(18)F]FEDAA1106 to TSPO in control subjects and AD patients. Seven controls (five men, two women, age 68±3 years, MMSE score 29±1) and nine AD patients (six men, three women, age 69±4 years, MMSE score 25±3) were studied with [(18)F]FEDAA1106. PET measurements were performed on an ECAT EXACT HR system (Siemens Medical Solutions) in two 60-min dynamic PET sessions with a 30-min interval between sessions. Arterial blood radioactivity was measured using an automated blood sampling system for the first 5 min and using manually drawn samples thereafter. Quantification was performed using both kinetic analysis based on a two-tissue compartment model and Logan graphical analysis. Outcome measures were total distribution volume (V T) and binding potential (BP(ND)=k3/k4). An estimate of nondisplaceable distribution volume was obtained with the Logan graphical analysis using the first 15 min of PET measurements (V(ND 1-15 min)). Binding potential (BP(ND)) was also calculated as: V(T)/V(ND 1-15 min) - 1. No statistically significant differences in V(T), k3/k4 or BP(ND) were observed between controls and AD patients. This study suggests that TSPO imaging with [(18)F]FEDAA1106 does not enable the detection of microglial activation in AD.