Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice.

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice.

Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead (RIPK1D138N/D138N) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL (Mlkl-/-) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH.

Stimulant Therapy in Acute Traumatic Brain Injury: Prescribing Patterns and Adverse Event Rates at 2 Level 1 Trauma Centers.

BACKGROUND/OBJECTIVE: Pharmacological stimulant therapies are routinely administered to promote recovery in patients with subacute and chronic disorders of consciousness (DoC). However, utilization rates and adverse drug event (ADE) rates of stimulant therapies in patients with acute DoC are unknown. We aimed to determine the frequency of stimulant use and associated ADEs in intensive care unit (ICU) patients with acute DoC caused by traumatic brain injury (TBI). METHODS: We retrospectively identified patients with TBI admitted to the ICU at 2 level 1 trauma centers between 2015 and 2018. Patients were included if they were stimulant naive at baseline and received amantadine, methylphenidate, or modafinil during ICU admission. Stimulant dose reduction or discontinuation during ICU admission was considered a surrogate marker of an ADE. Targeted chart review was performed to identify reasons for dose reduction or discontinuation. RESULTS: Forty-eight of 608 patients with TBI received pharmacological stimulant therapy (7.9%) during the study period. Most patients were diagnosed with severe TBI at presentation (60.4%), although stimulants were also administered to patients with moderate (14.6%) and mild (25.0%) TBI. The median time of stimulant initiation was 11 days post-injury (range: 2-28 days). Median Glasgow Coma Scale score at the time of stimulant initiation was 9 (range: 4-15). Amantadine was the most commonly prescribed stimulant (85.4%) followed by modafinil (14.6%). Seven (14.6%) patients required stimulant dose reduction or discontinuation during ICU admission. The most common ADE resulting in therapy modification was delirium/agitation (n = 2), followed by insomnia (n = 1), anxiety (n = 1), and rash (n = 1); the reason for therapy modification was undocumented in 2 patients. CONCLUSIONS: Pharmacological stimulant therapy is infrequently prescribed but well tolerated in ICU patients with acute TBI at level 1 trauma centers. These retrospective observations provide the basis for prospective studies to evaluate the safety, optimal dose range, and efficacy of stimulant therapies in this population.

Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury.

The neuroinflammatory response to traumatic brain injury (TBI) is critical to both neurotoxicity and neuroprotection, and has been proposed as a potentially modifiable driver of secondary injury in animal and human studies. Attempts to broadly target immune activation have been unsuccessful in improving outcomes, in part because the precise cellular and molecular mechanisms driving injury and outcome at acute, subacute, and chronic time points after TBI remain poorly defined. Microglia play a critical role in neuroinflammation and their persistent activation may contribute to long-term functional deficits. Activated microglia are characterized by morphological transformation and transcriptomic changes associated with specific inflammatory states. We analyzed the temporal course of changes in inflammatory genes of microglia isolated from injured brains at 2, 14, and 60 days after controlled cortical impact (CCI) in mice, a well-established model of focal cerebral contusion. We identified a time dependent, injury-associated change in the microglial gene expression profile toward a reduced ability to sense tissue damage, perform housekeeping, and maintain homeostasis in the early stages following CCI, with recovery and transition to a specialized inflammatory state over time. This later state starts at 14 days post-injury and is characterized by a biphasic pattern of IFNγ, IL-4, and IL-10 gene expression changes, with concurrent proinflammatory and anti-inflammatory gene changes. Our transcriptomic data sets are an important step to understand microglial role in TBI pathogenesis at the molecular level and identify common pathways that affect outcome. More studies to evaluate gene expression at the single cell level and focusing on subacute and chronic timepoint are warranted.