Inflammatory projections after focal brain injury trigger neuronal network disruption: An 18F-DPA714 PET study in mice

Abstract

Due to the heterogeneous pathology of traumatic brain injury (TBI), the exact mechanism of how initial brain damage leads to chronic inflammation and its effects on the whole brain remain unclear. Here, we report on long-term neuroinflammation, remote from the initial injury site, even after subsiding of the original inflammatory response, in a focal TBI mouse model. The use of translocator protein-positron emission tomography in conjunction with specialised magnetic resonance imaging modalities enabled us to visualize “previously undetected areas” of spreading inflammation after focal cortical injury. These clinically available modalities further revealed the pathophysiology of thalamic neuronal degeneration occurring as resident microglia sense damage to corticothalamic neuronal tracts and become activated. The resulting microglial activation plays a major role in prolonged inflammatory processes, which are deleterious to the thalamic network. In light of the association of this mechanism with neuronal tracts, we propose it can be termed “brain injury related inflammatory projection”. Our findings on multiple spatial and temporal scales provide insight into the chronic inflammation present in neurodegenerative diseases after TBI.

Long-Term Clinical and Neuronuclear Imaging Sequelae of Cancer Therapy, Trauma, and Brain Injury

“…For example, 11 C-PK11195 has demonstrated increased uptake in subcortical structures including the thalami, putamen, and parts of white matter in subjects with chronic single moderate to severe TBI (78). Furthermore, these findings have been replicated in additional studies using the second-generation translocator protein ligands 11 C-DPA-713, 18 F-DPA-714 (79), and 11 C-PBR28 (77).…”

Follow-up after 5.5 years of treatment with methylphenidate for mental fatigue and cognitive function after a mild traumatic brain injury

“…Chronic inflammation mainly in subcortical regions with increased microglial activation was present up to 17 years after a TBI (32). In an experimental mouse model of TBI, long-term microglial activation, remote from the initial injury site after a focal TBI was reported, and was suggested to have a major role in prolonged inflammatory processes and be deleterious to the thalamic network (33). Fatigue in neurological disorders has been suggested to be related to circuits that connect basal ganglia, amygdala, the thalamus and frontal cortex (34).…”

Basic Science of PET Imaging for Inflammatory Diseases

“…To evaluate traumatic brain injury (TBI) in small animals, a model of controlled cortical impact with a pneumatic impact device has been used for its high reproducibility and low mortality [112]. We reported two peaks of [ 18 F]DPA-714 uptake in this model, namely, on day 7 in the cortical area and on day 21 in the thalamus after induction of the focal brain injury [99]. The enhanced thalamic uptake was sustained until 14 weeks after induction of the TBI (Fig.…”

“…), and neuropsychiatric disorders (schizophrenia, autism spectrum disorder, etc.) [98][99][100][101]. In the central nervous system, two major glial cells are involved in the process of neuroinflammation, namely, microglia and astrocytes [99].…”

“…[ 98 – 101 ]. In the central nervous system, two major glial cells are involved in the process of neuroinflammation, namely, microglia and astrocytes [ 99 ]. To evaluate neuroinflammation in vivo, translocator protein (TSPO) has been the major target used in PET for the detection of neuroinflammation with glial activation [ 102 ].…”