The radioligand 18F-THK5351 was developed for imaging tau aggregates in NFTs in AD (Harada et al. 2016). Repetitive mild TBI can trigger the development of chronic traumatic encephalopathy (CTE), a progressive neurodegeneration characterized by the widespread deposition of hyperphosphorylated tau proteins as NFTs (McKee et al. 2009, 2013). In professional sports, there is increasing concern that football players and boxers with a history of repeated mild TBI might have an increased risk of developing CTE (McKee et al. 2009). There is a long latency period, usually 8–10 years, between an individual’s exposure to repetitive TBI and the appearance of clinical symptoms and tau aggregates in CTE (McKee et al. 2009). Therefore, the changes in 18F-THK5351 uptake in the present case are unlikely to be associated with tau aggregates in the injured brain after a single TBI.
TBI is characterized by initial brain damage caused by direct mechanical force and secondary damage due to subsequent pathophysiological processes. Following the initial injury, local microenvironment changes and damaged cells release intracellular components, triggering the activation and recruitment of resident glial cells in the injured brain. Among the resident glial cells in the brain, astrocytes are ubiquitous cells throughout brain tissue and play crucial roles in maintaining the homeostasis of ions, transmitters, water, and blood flow that are crucial for neuronal function in the brain (Chen and Swanson 2003). Astrocytes are pivotal responders to injury through diverse potential changes commonly referred to as reactive astrogliosis (Pekny and Nilsson 2005). TBI induces reactive astrocytes in and around the lesion site and is accompanied by a prominent increase in MAO-B expressions in reactive astrogliosis (Burda et al. 2016; Levitt et al. 1982). Both beneficial and detrimental roles have been attributed to reactive astrogliosis after TBI onset. For example, a potential tissue-protective effect could be provided by glutamate uptake, free radical scavenging or neurotrophin release, while potentially harmful effects might be caused by the release of pro-inflammatory cytokines or cytotoxic radicals (Chen and Swanson 2003). In the present case, 18F-THK5351 PET 46 days after the TBI showed a ring-like pattern tracer uptake around the brain contusions, suggesting that glial scar formation isolated the damaged area and restricted the spread of inflammatory cells and compounds, which would provide a favorable environment for surviving neurons.
At 271 days after the TBI, 18F-THK5351 PET showed reduced uptake of 18F-THK5351 in the original sites of brain contusions and increased tracer uptake in the white matter surrounding the brain contusions and the corpus callosum. A recent animal study showed that a single severe TBI resulted in a long-term, progressive inflammatory process with activated microglia and astrocytes (Pischiutta et al. 2018). This process not only involved the peri-lesional and ipsilateral hemisphere, but also extended to the contralateral hemisphere one year after injury, with particular involvement of white matter structures including the corpus callosum (Pischiutta et al. 2018). Increased uptake of 18F-THK5351 within the corpus callosum in the chronic phase is of particular interest, as this structure represents a region highly susceptible to TBI, suggesting that active neuroinflammatory events driven by reactive astrogliosis are continued at this time. This finding reflects clinical observations in moderate to severe TBI patients: an ongoing neuroinflammatory response was evident in the corpus callosum in about one-third of the patients surviving a year or more after a single TBI (Johnson et al. 2013). There are increasing evidence that reactive astrocytes also play crucial roles in post-TBI synaptic plasticity and the reorganization of the neuronal circuits (Burda et al. 2016). Astrocytes have a dual (promoting or suppressing) role in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, and repair of the blood–brain barrier after TBI (Zhou et al. 2020). The overall effects of sustained reactive astrogliosis after TBI have not been fully elucidated and may vary with injury intensity, distance from lesions, and stage of injury. Other cells such as brain-resident microglia are also activated after TBI. Both astrocytes and microglia react within 24 h and peak around day 3–7; however, microglia rapidly decline to control levels approximately 21 days, while astrocytes exhibited a long-lasting activation, at least, 28 days after TBI (Jassam et al. 2017). Studies have shown that the 18 kDa translocator protein (TSPO) expression is upregulated in activated microglia cells in response to inflammation or injury to the brain and many radioligands have been synthesized for TSPO imaging (Tronel et al. 2017). A multi-targets approach of PET imaging for astrocytes and microglia activation can help to characterize the involvement of neuroinflammation after TBI.
Recently, Ishibashi et al. reported a case of cerebral infarction in which astrogliosis in the lesion was monitored by 18F-THK5351 PET on days 27 and 391. The uptake of 18F-THK5351 in the infarct lesion decreased significantly between the two PET examinations (Ishibashi et al. 2020). The change in 18F-THK5351 uptake in the infarct lesion was different from our case, suggesting that different brain pathologies induce different spatial and temporal changes in reactive astrogliosis.