Combined [18F]DPA-714 micro-positron emission tomography and autoradiography imaging of microglia activation after closed head injury in mice

Ina Israel,Christoph Kleinschnitz,Andreas K. Buck,Christian Stetter,Samuel Samnick,Anna-Leena Sirén,Ehab Al-Momani,Christiane Albert-Weissenberger,Stine Mencl,Andrea Ohsiek

doi:10.1186/s12974-016-0604-9

Ina Israel, Christoph Kleinschnitz + Show 8 more

Open Access

https://doi.org/10.1186/s12974-016-0604-9

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Abstract

BackgroundTraumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry.MethodsA weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [18F]DPA-714 was performed on day 1, 7, and 16 and [18F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [18F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [18F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1.ResultsFunctional outcome correlated with focal brain lesions, gliosis, and axonal injury. [18F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [18F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [18F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [18F]DPA-714 was not increased in autoradiography or in μPET imaging.Conclusions[18F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.

Highlights

Traumatic brain injury (TBI) is a major cause of death and disability
Even though improved emergency and hospital care have reduced the acute mortality of TBI, surviving patients often live with severe disabilities and develop progressive brain damage or dementia of unknown origin [3]
Before use, [18F]DPA-714 and [18F]FDG were analyzed by highperformance liquid chromatography (HPLC) for radiochemical purity and sterile filtered through a 0.22-μm sterile filter

Summary

Introduction

Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. As the inflammatory responses after TBI are complex and probably reflect the heterogeneity of injury mechanism and comorbidities in the TBI population [3,4,5], a better characterization of the spatial and temporal evolution of inflammation by repeated intra-individual monitoring is needed for the development of targeted therapies In this context, repeated in vivo positron emission tomography (PET) imaging of neuroinflammation represents a powerful tool and in combination with autoradiography enables resolution at the cellular level [5,6,7,8,9,10,11]

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