Neuroimaging of translocator protein in patients with systemic lupus erythematosus: a pilot study using [11C]DPA-713 positron emission tomography

Objective Inflammation secondary to autoantibody-mediated effects occurring in multiple organs is a hallmark of systemic lupus erythematosus (SLE). The inflammatory response to SLE-mediated damage in brain parenchyma has been postulated in both normal and cognitively impaired individuals. Our goal is to use molecular imaging to investigate the distribution within the brain of the mitochondrial translocator protein (TSPO) that is upregulated during glial cell activation, and is considered as a marker of brain injury and repair. Methods We sought to characterize TSPO distribution in the brain of SLE patients using positron emission tomography (PET) and [11C]DPA-713 (DPA), a radiopharmaceutical that targets TSPO. We imaged 11 healthy controls and 10 patients with SLE (years of diagnosis: 13.0 ± 7.7), all between the ages of 22 and 52. Results: Among the nine brain regions studied, no statistically significant increases in DPA binding were observed in SLE. Instead, there was a significant decrease in TSPO distribution in the cerebellum and hippocampus of SLE patients, as compared to healthy controls. Such decreases were most significant in cognitively normal SLE subjects, but showed pseudo-normalization in those with cognitive impairment, due to higher cerebellar and hippocampal DPA binding in the cognitively impaired (versus normal) SLE brain. Conclusions Results from this pilot study suggest a link between diminished regional TSPO expression in the brain of patients with SLE, as well as possible glial cell activation within the cerebellum and hippocampus of cognitively impaired individuals with SLE. Further studies are needed to elucidate how mitochondrial dysfunction and glial cell activation may act together in SLE and SLE-mediated neurocognitive deficits.

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Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05327-x ◽

2021 ◽

Author(s):

Tiago Reis Marques ◽

Mattia Veronese ◽

David R. Owen ◽

Eugenii A. Rabiner ◽

Graham E. Searle ◽

...

Keyword(s):

Outcome Measure ◽

Specific Binding ◽

Specific Protein ◽

Translocator Protein ◽

Emission Tomography ◽

Single Subject ◽

Healthy Controls ◽

Positron Emission ◽

Pet Scans ◽

The Brain

Abstract Objective The mitochondrial 18-kDa translocator protein (TSPO) is expressed by activated microglia and positron emission tomography enables the measurement of TSPO levels in the brain. Findings in schizophrenia have shown to vary depending on the outcome measure used and this discrepancy in TSPO results could be explained by lower non-displaceable binding (VND) in schizophrenia, which could obscure increases in specific binding. In this study, we have used the TSPO ligand XBD173 to block the TSPO radioligand [11C]-PBR28 and used an occupancy plot to quantify VND in patients with schizophrenia. Methods A total of 7 patients with a diagnosis of schizophrenia were recruited for this study. Each patient received two separate PET scans with [11C]PBR28, one at baseline and one after the administration of the TSPO ligand XBD173. All patients were high-affinity binders (HABs) for the TSPO gene. We used an occupancy plot to quantify the non-displaceable component (VND) using 2TCM kinetic estimates with and without vascular correction. Finally we computed the VND at a single subject level using the SIME method. Results All patients showed a global and generalized reduction in [11C]PBR28 uptake after the administration of XBD173. Constraining the VND to be equal for all patients, the population VND was estimated to be 1.99 mL/cm3 (95% CI 1.90 to 2.08). When we used vascular correction, the fractional TSPO occupancy remained similar. Conclusions In schizophrenia patients, a substantial component of the [11C]PBR28 signal represents specific binding to TSPO. Furthermore, the VND in patients with schizophrenia is similar to that previously reported in healthy controls. These results suggest that changes in non-specific binding between schizophrenia patients and healthy controls do not account for discrepant PET findings in this disorder.

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From positron emission tomography to cell analysis of the 18-kDa Translocator Protein in mild traumatic brain injury

Scientific Reports ◽

10.1038/s41598-021-03416-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Clément Delage ◽

Nicolas Vignal ◽

Coralie Guerin ◽

Toufik Taib ◽

Clément Barboteau ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Positron Emission Tomography ◽

Flow Cytometry ◽

Microglial Activation ◽

Translocator Protein ◽

Emission Tomography ◽

Flow Cytometry Analysis ◽

Positron Emission ◽

The Brain ◽

Tspo Expression

AbstractTraumatic brain injury (TBI) leads to a deleterious neuroinflammation, originating from microglial activation. Monitoring microglial activation is an indispensable step to develop therapeutic strategies for TBI. In this study, we evaluated the use of the 18-kDa translocator protein (TSPO) in positron emission tomography (PET) and cellular analysis to monitor microglial activation in a mild TBI mouse model. TBI was induced on male Swiss mice. PET imaging analysis with [18F]FEPPA, a TSPO radiotracer, was performed at 1, 3 and 7 days post-TBI and flow cytometry analysis on brain at 1 and 3 days post-TBI. PET analysis showed no difference in TSPO expression between non-operated, sham-operated and TBI mice. Flow cytometry analysis demonstrated an increase in TSPO expression in ipsilateral brain 3 days post-TBI, especially in microglia, macrophages, lymphocytes and neutrophils. Moreover, microglia represent only 58.3% of TSPO+ cells in the brain. Our results raise the question of the use of TSPO radiotracer to monitor microglial activation after TBI. More broadly, flow cytometry results point the lack of specificity of TSPO for microglia and imply that microglia contribute to the overall increase in TSPO in the brain after TBI, but is not its only contributor.

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Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Biological Psychiatry ◽

10.1016/j.biopsych.2018.02.1171 ◽

2018 ◽

Vol 84 (6) ◽

pp. 433-442 ◽

Cited By ~ 43

Author(s):

Pontus Plavén-Sigray ◽

Granville J. Matheson ◽

Karin Collste ◽

Abhishekh H. Ashok ◽

Jennifer M. Coughlin ◽

...

Keyword(s):

Positron Emission Tomography ◽

Glial Cell ◽

Meta Analysis ◽

Translocator Protein ◽

Emission Tomography ◽

Individual Participant Data ◽

Cell Marker ◽

Positron Emission ◽

Individual Participant

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Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11C-PBR28 MR-PET

Multiple Sclerosis Journal ◽

10.1177/1352458519843048 ◽

2019 ◽

Vol 26 (6) ◽

pp. 668-678 ◽

Cited By ~ 5

Author(s):

Valeria T Barletta ◽

Elena Herranz ◽

Costantina A Treaba ◽

Russell Ouellette ◽

Ambica Mehndiratta ◽

...

Keyword(s):

Positron Emission Tomography ◽

Tracer Uptake ◽

Emission Tomography ◽

7 Tesla ◽

Healthy Controls ◽

Multilinear Regression ◽

Neurological Disability ◽

Standardized Uptake Values ◽

Positron Emission ◽

The Brain

Background: Activated microglia, which can be detected in vivo by 11C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. Methods: Twenty-eight MS patients and 16 healthy controls underwent 11C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11C-PBR28 binding was assessed in regions of interest using 60–90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.

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In vivo PET imaging of neuroinflammation in familial frontotemporal dementia

10.1101/2020.05.11.20098046 ◽

2020 ◽

Cited By ~ 1

Author(s):

Maura Malpetti ◽

Timothy Rittman ◽

P Simon Jones ◽

Thomas E Cope ◽

Luca Passamonti ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Regional Distribution ◽

Case Series ◽

Emission Tomography ◽

Healthy Controls ◽

Disease Modification ◽

Positron Emission ◽

Immunomodulatory Therapies ◽

The Brain

INTRODUCTION: We report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia with mutations in MAPT, GRN and C9orf72 genes. METHODS: Using positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligand [11C]PK11195, and the regional distribution of tau- or TDP-43 pathology, indexed using the radioligand [18F]AV-1451. The familial FTD PET data were compared to healthy controls. RESULTS: Familial FTD patients across all mutation groups showed increased [11C]PK11195 binding predominantly in frontotemporal regions, with additional regions showing abnormalities in individuals. Patients with MAPT mutations had a consistent distribution of [18F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations. DISCUSSION: This case series suggests a consistent role for neuroinflammation in the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.

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In vivo PET imaging of neuroinflammation in familial frontotemporal dementia

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323698 ◽

2020 ◽

pp. jnnp-2020-323698 ◽

Cited By ~ 1

Author(s):

Maura Malpetti ◽

Timothy Rittman ◽

Peter Simon Jones ◽

Thomas Edmund Cope ◽

Luca Passamonti ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Regional Distribution ◽

Case Series ◽

Emission Tomography ◽

Healthy Controls ◽

Disease Modification ◽

Positron Emission ◽

Immunomodulatory Therapies ◽

The Brain

IntroductionWe report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia (FTD) with mutations in MAPT, GRN and C9orf72 genes.MethodsUsing positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligand [11C]PK11195, and the regional distribution of tau or TDP-43 pathology, indexed using the radioligand [18F]AV-1451. The familial FTD PET data were compared with healthy controls.ResultsPatients with familial FTD across all mutation groups showed increased [11C]PK11195 binding predominantly in frontotemporal regions, with additional regions showing abnormalities in individuals. Patients with MAPT mutations had a consistent distribution of [18F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations.DiscussionThis case series suggests that neuroinflammation is part of the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.

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TSPO: an emerging role in appetite for a therapeutically promising biomarker

Open Biology ◽

10.1098/rsob.210173 ◽

2021 ◽

Vol 11 (8) ◽

pp. 210173

Author(s):

Joshua Wang ◽

Kate Beecher

Keyword(s):

Positron Emission Tomography ◽

Side Effect ◽

Western Diet ◽

Translocator Protein ◽

Emission Tomography ◽

Side Effect Profile ◽

Synaptic Protein ◽

Diet Induced Obesity ◽

Positron Emission ◽

The Brain

There is accumulating evidence that an obesogenic Western diet causes neuroinflammatory damage to the brain, which then promotes further appetitive behaviour. Neuroinflammation has been extensively studied by analysing the translocator protein of 18 kDa (TSPO), a protein that is upregulated in the inflamed brain following a damaging stimulus. As a result, there is a rich supply of TSPO-specific agonists, antagonists and positron emission tomography ligands. One TSPO ligand, etifoxine, is also currently used clinically for the treatment of anxiety with a minimal side-effect profile. Despite the neuroinflammatory pathogenesis of diet-induced obesity, and the translational potential of targeting TSPO, there is sparse literature characterizing the effect of TSPO on appetite. Therefore, in this review, the influence of TSPO on appetite is discussed. Three putative mechanisms for TSPO's appetite-modulatory effect are then characterized: the TSPO–allopregnanolone–GABA A R signalling axis, glucosensing in tanycytes and association with the synaptic protein RIM-BP1. We highlight that, in addition to its plethora of functions, TSPO is a regulator of appetite. This review ultimately suggests that the appetite-modulating function of TSPO should be further explored due to its potential therapeutic promise.

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Longitudinal positron emission tomography imaging of glial cell activation in a mouse model of mesial temporal lobe epilepsy: Toward identification of optimal treatment windows

Epilepsia ◽

10.1111/epi.14083 ◽

2018 ◽

Vol 59 (6) ◽

pp. 1234-1244 ◽

Cited By ~ 18

Author(s):

Duc-Loc Nguyen ◽

Catriona Wimberley ◽

Charles Truillet ◽

Benoit Jego ◽

Fabien Caillé ◽

...

Keyword(s):

Positron Emission Tomography ◽

Mouse Model ◽

Cell Activation ◽

Positron Emission Tomography Imaging ◽

Mesial Temporal Lobe Epilepsy ◽

Emission Tomography ◽

Tomography Imaging ◽

Glial Cell Activation ◽

Positron Emission ◽

Mesial Temporal Lobe

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SARS-CoV-2 Spike Protein Induces Cognitive Deficit and Anxiety-like Behavior in Mouse via Non-cell Autonomous Hippocampal Neuronal Death

10.21203/rs.3.rs-1190472/v1 ◽

2022 ◽

Author(s):

Sung Joong Lee ◽

Jun Young Oh ◽

Woo-Hyun Cho ◽

Barcelon Ellane ◽

Kwang Hwan Kim ◽

...

Keyword(s):

Cell Death ◽

Glial Cell ◽

Neuronal Death ◽

Cell Activation ◽

Cognitive Deficit ◽

Neuronal Cell ◽

Neurological Symptoms ◽

Spike Protein ◽

Glial Cell Activation ◽

The Brain

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accompanied by chronic neurological sequelae such as cognitive decline and mood disorder, but the underlying mechanisms have not yet been elucidated. In this study, we explored the possibility that the brain-infiltrating SARS-CoV-2 spike protein contributes to the development of neurological symptoms observed in COVID-19 patients. Our behavioral study showed that administration of SARS-CoV-2 spike protein S1 subunit (S1 protein) to mouse hippocampus induced cognitive deficit and anxiety-like behavior in vivo. These neurological symptoms were accompanied by neuronal cell death in the dorsal and ventral hippocampus as well as glial cell activation. Interestingly, the S1 protein did not directly induce hippocampal cell death in vitro. Rather, it exerted neurotoxicity via glial cell activation, partially through interleukin-1β induction. In conclusion, our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.

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