Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation

Vicente-Rodríguez, Marta; Singh, Nisha; Turkheimer, Federico; Peris-Yague, Alba; Randall, Karen; Veronese, Mattia; Simmons, Camilla; Haji-Dheere, Abdul Karim; Bordoloi, Jayanta; Sander, Kerstin; Awais, Ramla O.; Årstad, Erik; Cash, Diana; Parker, Christine A.

doi:10.1016/j.bbi.2021.05.025

Cited by 21 publications

(19 citation statements)

References 71 publications

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“…Our data show that peripherally-induced neuroinflammation can be reliably detected in the CNS using the TSPO-PET radioactive tracer [18F] DPA-714. Our results supported the conclusion that the resulting increase in [18F] DPA-714 TSPO signaling is primarily attributable to a combination of microglia, astrocytes, and monocyte-derived macrophages [ 33 ]. This study focused on the expression of the DPA-714 signal in glial cells.…”

Section: Discussionsupporting

confidence: 88%

Dynamic Microglial Activation is Associated with LPS-induced Depressive-like Behavior in Mice: An [18F] DPA-714 PET Imaging Study

Qiu

Guo

Wang

et al. 2022

Bosn J of Basic Med Sci

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Major depressive disorder (MDD) is a highly pervasive, severe psychological condition for which the precise underlying pathophysiology is incompletely understood, although microglial activation is known to play a role in this context. In this study we analyzed the association between neuroinflammation and depressive-like behaviors in a lipopolysaccharide (LPS)-induced mouse model system using 10-12-week-old male C57BL/6 mice. Microglial activation and associated neuroinflammatory activity were monitored via positron emission tomography (PET) imaging. Animals were assessed at three time points, including 24 h prior to LPS injection, 24 h post-LPS injection, and 72 h post-LPS injection. Analyses of microglial activation and hippocampal neuroinflammation were conducted through [18]F DPA-714 PET imaging and immunohistochemical staining for ionized calcium-binding adapter molecule 1 (Iba-1) and translocator protein (TSPO). Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome activity and interleukin-1β (IL-1β) levels were assessed at 24 h post-LPS injection. We found that LPS treatment was associated with a marked increase in depressive-like behavior at 24 h post-injection time point, and that it was less pronounced at the 72 h post-injection time point. These changes coincided with enhanced [18F] DPA-714 PET uptake in the whole brain, hippocampus, cortex and amygdala together with increased hippocampal microglial activation as evidenced by immunofluorescent staining. By 72 h post-injection, however, these PET and immunofluorescence phenotypes had returned to baseline levels. Furthermore, increased NLRP3 inflammasome activation and IL-1β expression were evident at 24 h post-LPS injection. These data demonstrate that dynamic microglial activation is associated with LPS-induced depressive-like behaviors and hippocampal neuroinflammation in a mouse model system.

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Section: Discussionsupporting

confidence: 88%

Dynamic Microglial Activation is Associated with LPS-induced Depressive-like Behavior in Mice: An [18F] DPA-714 PET Imaging Study

Qiu

Guo

Wang

et al. 2022

Bosn J of Basic Med Sci

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“…TSPO signal in the hippocampus reportedly arises from microglia and astrocytes, whereas microglia, macrophages and astrocytes are the main contributors in the substantia nigra. 59 In this work, evaluation was exclusive to the frontal cortex which may have characteristically unique TSPO cellular origin. These immunostaining studies show that it is imperative to investigate TSPO expression in human tissue acquired from diseased patients compared with controls.…”

Section: Discussionmentioning

confidence: 99%

“…TSPO expression has been reportedly regulated by a variety of factors including immune cell activation state, neuronal activity and ROIs studied. 55 , 59 , 63 The inconsistencies with TSPO expression between neuroinflammatory conditions contribute to the need for additional neuroinflammation imaging targets with higher specificity than TSPO towards CTE.…”

Section: Discussionmentioning

confidence: 99%

Characterization of neuroinflammatory positron emission tomography biomarkers in chronic traumatic encephalopathy

Varlow

Knight

McQuade

et al. 2022

Brain Communications

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Chronic traumatic encephalopathy is a neurological disorder associated with head trauma and is confirmed upon autopsy. PET imaging of chronic traumatic encephalopathy may provide a means to move toward ante-mortem diagnosis and therapeutic intervention following brain injuries. Characterization of the neuroinflammatory PET biomarkers, 18 kDa translocator protein and monoamine oxidase-B was conducted using [3H]PBR-28 and [3H]L-deprenyl, respectively, in post-mortem chronic traumatic encephalopathy brain tissue. [3H]PBR-28 displayed high specific binding in both chronic traumatic encephalopathy (95.40 ± 1.87%; n = 11 cases) and healthy controls (89.89 ± 8.52%, n = 3 cases). Cell-type expression of the 18 kDa translocator protein was confirmed by immunofluorescence to microglia, astrocyte and macrophage markers. [3H]L-deprenyl also displayed high specific binding in chronic traumatic encephalopathy (96.95 ± 1.43%; n = 12 cases) and healthy controls (93.24 ± 0.43%; n = 2 cases), with the distribution co-localized to astrocytes by immunofluorescence. Saturation analysis was performed to quantify the target density of the 18 kDa translocator protein and monoamine oxidase-B in both chronic traumatic encephalopathy and healthy control tissue. Using [3H]PBR-28 the target density of the 18 kDa translocator protein in healthy controls was 177.91 ± 56.96 nM (n = 7 cases; mean ± SD) however, a highly variable target density (345.84 ± 372.42 nM; n = 11 cases; mean ± SD) was measured in chronic traumatic encephalopathy. [3H]L-deprenyl quantified an monoamine oxidase-B target density of 304.23 ± 115.93 nM (n = 8 cases; mean ± SD) in healthy control tissue and is similar to the target density in chronic traumatic encephalopathy tissues (365.80 ± 128.55 nM; n = 12 cases; mean ± SD). A two-sample t-test determined no significant difference in the target density values of the 18 kDa translocator protein and monoamine oxidase-B between healthy controls and chronic traumatic encephalopathy (P > 0.05), albeit a trend towards increased expression of both targets was observed in chronic traumatic encephalopathy. To our knowledge, this work represents the first in vitro characterization of 18 kDa translocator protein and monoamine oxidase-B in chronic traumatic encephalopathy and reveals the variability in neuroinflammatory pathology following brain injuries. These preliminary findings will be considered when designing PET imaging studies after brain injury, and for the ultimate goal of imaging chronic traumatic encephalopathy in vivo.

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“…A limitation of the use of TSPO PET imaging techniques to measure brain inflammation is that it is unclear what cell type is responsible for the TSPO binding signal. For many years, TSPO was thought to be specific to microglial activation, yet TSPO can also be bound by other inflammatory cells, including astrocytes and peripheral immune cells 73-76 . More recent studies in rodent models have suggested that TSPO signal may be related more to microglial number than microglial activation 77 .…”

Section: Discussionmentioning

confidence: 99%

Brain and systemic inflammation in de novo Parkinson’s disease

Yacoubian

Fang

Gerstenecker

et al. 2022

Preprint

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Objective: To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson disease (PD). Background: Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation, and whether pro-inflammatory signals are associated with clinical features or predict more rapid progression. Methods: We enrolled subjects with de novo PD (n=58) and age-matched controls (n=62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment (MCI) testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18F-DPA-714, a translocator protein 18kd (TSPO) ligand, and lumbar puncture if eligible and consented. Results: Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. PET imaging showed increased 18F-DPA-714 signal in PD subjects. 18F-DPA-714 signal correlated with several cognitive measures and some chemokines. Conclusions: 18F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline.

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Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation

Cited by 21 publications

References 71 publications

Dynamic Microglial Activation is Associated with LPS-induced Depressive-like Behavior in Mice: An [18F] DPA-714 PET Imaging Study

Dynamic Microglial Activation is Associated with LPS-induced Depressive-like Behavior in Mice: An [18F] DPA-714 PET Imaging Study

Characterization of neuroinflammatory positron emission tomography biomarkers in chronic traumatic encephalopathy

Brain and systemic inflammation in de novo Parkinson’s disease

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