A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis

Nutma, Erik; Stephenson, Jodie; Gorter, Rianne P.; Bruin, Joy de; Boucherie, Deirdre M; Donat, Cornelius K.; Breur, Marjolein; Valk, Paul van der; Matthews, Paul M.; Owen, David R.; Amor, Sandra

doi:10.1093/brain/awz287

Cited by 83 publications

(96 citation statements)

References 95 publications

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“…Regarding the validity of the tracer, we were encouraged by a recent detailed report finding a strong correlation between [3H]PBR28 radioligand binding in vitro (the tritiated version of the tracer we used) and the number of TSPO‐positive cells across all CNS tissues examined. These include microglia and macrophages and also activated astrocytes (and in smaller measure endothelial cells) in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Although suspected, meningeal inflammation has never been documented in a population of migraineurs. Most clinical studies in migraineurs measure blood flow, vessel caliber, or blood oxygen level dependent responses within brain, and rarely within meninges, hence the importance and novelty of this study using a 2nd generation positron emission tomography (PET) ligand, 11 C‐PBR28, that detects activated inflammatory cells (reviewed in Albrecht et al, Nutma et al). Its binding site, the 18kD translocator protein (TSPO), is located on outer mitochondrial membranes.…”

Section: Introductionmentioning

confidence: 99%

“…Its binding site, the 18kD translocator protein (TSPO), is located on outer mitochondrial membranes. Previously known as the peripheral benzodiazepine receptor, TSPO, expressed at low levels in healthy central nervous system (CNS) tissue, is often used as a marker of glial activation within brain parenchyma, reflecting activated microglia and/or astrocytes in multiple animal models of disease as well as humans …”

Section: Introductionmentioning

confidence: 99%

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Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Hadjikhani

Albrecht

Mainero

et al. 2020

Annals of Neurology

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Objective: Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. Methods: We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). Results: MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT.Interpretation: A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Hadjikhani

Albrecht

Mainero

et al. 2020

Annals of Neurology

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“…In this study we have developed an original post-processing pipeline of 18 A key finding of this study was the large amount of WM lesions classified as "active" based on 18 F-DPA-714 PET (37,1% of T2 lesions), which were completely invisible to Gd+ MRI sequences (only 0.2% of T2 lesions). These results suggest that our original processing of 18 A careful interpretation of our results is required with regard to the suboptimal specificity of TSPO tracers, which are known to bind to active innate immune cells, but also to astrocytes and endothelial cells (15,28). Moreover, in our study we defined a threshold to classify DPA+ voxels, which depends on the same patients to whom it was then applied, and this might constitute a possible bias.…”

Section: Discussionmentioning

confidence: 96%

Individual Mapping of Innate Immune Cell Activation Is a Candidate Marker of Patient-Specific Trajectories of Worsening Disability in Multiple Sclerosis

et al. 2020

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To develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using 18 F-DPA-714 translocator protein (TSPO) positron emission tomography (PET), and to explore the relationship between these maps and individual trajectories of disability worsening in patients with multiple sclerosis (MS). Methods: Patients with MS (n=37), whose trajectories of disability worsening over the 2 years preceding study entry were calculated, and healthy controls (n=19) underwent magnetic resonance magnetic and 18 F-DPA-714 PET. A threshold of significant activation of 18 F-DPA-714 binding was calculated with a voxel-wise randomized permutation-based comparison between patients and controls, and used to classify each WM voxel in patients as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were employed to calculate the extent of activation in WM regions-of-interests and to classify each WM lesion as "DPA-active", "DPA-inactive" or "unclassified". Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM, (NAWM in patients=24.99.7%; WM in controls=14.07.8%, p<0.001). In patients with MS, the percentage of DPA+ voxels showed a significant increase from NAWM, to perilesional areas, T2 hyperintense lesions and T1 hypointense lesions (38.113.5%, 45.017.9%, and 51.922.9%, respectively, p<0.001). Among the 1379 T2 lesions identified, 512 were defined as DPAactive and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (OR=1.13, p=0.009), a higher percentage of DPA+ voxels in the NAWM (OR=1.16, p=0.009) and in T1-spin-echo lesions (OR=1.06, p=0.036), were significantly associated by Imperial College London Library on February 11, 2020. For personal use only. jnm.snmjournals.org Downloaded from 2 with a retrospective more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with an innate immune cells activation inside and around WM lesions. 18 F-DPA-714 PET may provide a promising biomarker to identify patients at risk of severe clinical trajectory.

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“…To determine whether increases in TSPO uptake detected by PET-imaging in these mice correlated with measures in brain tissue at the 16-week study endpoint, double-label IHC was performed to detect cells labeling for TSPO + (red color) and/or Iba-1 + microglia (brown color). There are relatively few published studies that have analyzed TSPO expression in brain tissue in conjunction with neuroimaging (31)(32)(33)(34). We rst conducted a qualitative survey of brain sections from each group of mice.…”

Section: Tspo-iba-1 Immunoreactivity Is Abundant In Cortical and Hmentioning

confidence: 99%

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

Mahmud

Greif

et al. 2020

Preprint

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Background Osteopontin (OPN) as a secreted signaling protein, is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts, poorly understood. Methods Positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain, is a non-invasive tool used to track neuroinflammation in living mammals. Results In humanized, chronically HIV-infected mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand, DPA-713 was markedly upregulated in the hippocampus, cortex, olfactory bulb, cerebellum and significantly increased in other key brain regions analyzed compared to controls. TSPO+ microglia were detected by immunolabeling of post-mortem brain tissue, thus validating the neuroimaging findings. Unexpectedly, two types of neurons also selectively stained positively for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase positive neurons of the substantia nigra. Two-way ANOVA of immunoreactivity revealed that a well-validated marker of microglial activation in brain tissue, ionized calcium-binding adaptor molecule-1 (Iba-1) was significantly increased, in an interaction that depended on HIV replication. Interestingly, similar analyses of TSPO immunoreactivity showed a significant interaction with OPN expression. Conclusions Collectively, these findings using a model of chronic HIV-infection revealed for the first time two key findings: 1) two different pathways of neuroinflammation are activated, and 2) osteopontin acts as a molecular brake regulating in the brain, the inflammatory response to HIV infection.

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A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis

Cited by 83 publications

References 95 publications

Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Individual Mapping of Innate Immune Cell Activation Is a Candidate Marker of Patient-Specific Trajectories of Worsening Disability in Multiple Sclerosis

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

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