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

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.

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

“…Investigations using second-generation ligands fully support the results of the increased uptake in different types of trauma but are in contrast with the findings of increases of TSPO expression early after traumatic events [50]. Namely, studies have observed significant elevations of TSPO BP using 18F-DPA-714 as early as 2 days after the injury, with a proportional increase for at least 16 days in animal models [177,178]. The same results were obtained with 3H-PK11195 and 18F-fluoroethyl-DAA1106 in brain regions not primarily affected by cranial damage [179,180].…”

Brain microglia in psychiatric disorders

“…TSPO is a five-membrane domain protein localized mainly in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central nervous system, endothelial and glial cells in particular 16 One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis 17 Peripheral LPS injection in human primates has been shown to increase TSPO expression in a uniform manner across the brain. 18 Elevation in TSPO levels is associated with microglial activation and is robustly associated with Ionised calcium adaptor binding protein -1 (Iba1) positive cells in pre-clinical model as well as histological markers of brain activation in human post-mortem tissue [19][20][21] [ 11 C]-(R) PK11195 is one of the main radiotracers that have been used to study brain TSPO expression in vivo. However, given the increasing interest in studying neuroinflammation in vivo, a number of second-generation TSPO radiotracers have been developed with increased affinity and possibly improved signal-to-noise ratio.…”

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

“…TSPO positron emission tomography (PET) is currently a reference tool for monitoring neuroinflammation involved in many brain diseases such as Alzheimer disease, stroke, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, and brain tumors . There have also been studies in humans reporting increased TSPO binding in different types of epilepsy such as Rasmussen encephalitis, focal cortical dysplasia, and mesial temporal lobe epilepsy (MTLE) .…”

“…9 TSPO is expressed at low levels in healthy brain but is markedly increased at sites of brain injury and inflammation, making it of great interest as a biomarker for the study of diseases that include a component of neuroinflammation. 10 TSPO positron emission tomography (PET) is currently a reference tool for monitoring neuroinflammation involved in many brain diseases such as Alzheimer disease, 11 stroke, 12 traumatic brain injury, 13 multiple sclerosis, 14 amyotrophic lateral sclerosis, 15 and brain tumors. 16 There have also been studies in humans reporting increased TSPO binding in different types of epilepsy such as Rasmussen encephalitis, 17 focal cortical dysplasia, 4 and mesial temporal lobe epilepsy (MTLE).…”