Cognitive disorder after traumatic brain injury
Cognitive impairment and post-concussive symptoms (PCS) represent hallmark sequelae of pediatric mild traumatic brain injury (pmTBI).
Cognitive disorder after traumatic brain injury contribute to the morbidity and loss of productivity of over 10 million people worldwide.
They can lead to devastating consequences for both patients and their families.
Etiology
An ongoing chronic inflammatory response after TBI is thought to be an important factor in driving this cognitive decline.
Mallah et al. investigated the role of complement in neuroinflammation and cognitive decline for up to 6 months after murine TBI. Male C57BL/6 mice were subjected to open head injury using a controlled cortical impact device. At 2 months post-TBI, mice were moved to large cages with an enriched environment to simulate rehabilitation therapy and assigned to one of three treatment groups: 1. vehicle (PBS), 2. CR2Crry (3 doses over 1 week), 3. CR2Crry (continuous weekly dose until the end of the study). The study was terminated at 6 months post-TBI for all groups. Motor and cognitive function were analyzed, with histopathological analysis of brain tissue. Measured at 6 months after TBI, neither of the complement inhibition paradigms improved motor performance. However, mice receiving continuous CR2Crry treatment showed improved spatial learning and memory compared to both mice receiving only 3 doses and to mice receiving vehicle control. Analysis of brain sections at 6 months after injury revealed ongoing complement activation in the control group, with reduced complement activation and C3 deposition in the continuous CR2Crry treatment group. The ipsilateral hemisphere of continuously treated animals also showed a decrease in microglia/macrophage and astrocyte activation compared to vehicle. There was also increased astrocytosis in the contralateral hippocampus of vehicle-treated vs. naïve mice, which was reduced in mice continuously treated with CR2Crry. This study demonstrates continued complement-mediated neuroinflammation at extended chronic time points after TBI, and extends the potential treatment window for complement inhibition, which has previously been shown to improve outcomes after murine TBI 1).
The high prevalence of cognitive disabilities is due, in part, to the vulnerability of the hippocampus, which exhibits bilateral atrophy years after the initial trauma even when not directly injured 2) 3).
TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI.
SIGNIFICANCE STATEMENT: Currently, there are an estimated 3.2-5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of 10 of these individuals report cognitive disabilities (Thurman et al., 1999; Lew et al., 2006; Zaloshnja et al., 2008). One of the molecular mechanisms associated with chronic cognitive disabilities is impaired cAMP signaling in the hippocampus. In this study, we report that a selective phosphodiesterase 4B (PDE4B) inhibitor reduces chronic cognitive deficits after TBI and rescues deficits in hippocampal long-term potentiation. These results suggest that PDE4B inhibition has the potential to improve learning and memory ability and overall functioning for people living with TBI 4).
Wang and Li hypothesize that neuron loss, diffuse axonal injury, microbleed, and blood-brain barrier (BBB) disruption altogether contribute to the development of cognitive impairment. Furthermore, the disruption of structural and functional neural network related to the cognitive function might bring about the final step in the occurrence of cognitive impairment after TBI. In this review, Wang and Li summarize the role of different MRI techniques in the assessment of the pathological changes related to cognitive impairment after TBI. These MRI techniques include T1-MPRAGE sequence reflecting neuron loss, diffusion tensor imaging reflecting diffuse axonal injury, diffusion kurtosis imaging reflecting diffuse axonal injury and reactive gliosis, susceptibility weighted imaging showing microbleed, arterial spin labeling showing blood flow and dynamic contrast enhanced MRI showing BBB disruption. In the future, correlational study of multi-MRI sequences scan, pathological examination, and cognitive tests will provide valuable information for understanding the mechanism of cognitive impairment after TBI and manage TBI patients 5).
The underlying neurological basis for TBI-induced cognitive dysfunction remains unknown. However, many lines of research have implicated the hippocampus in the pathophysiology of TBI. In particular, past research has found that theta oscillations, long thought to be the electrophysiological basis of learning and memory, are decreased in the hippocampus post-TBI. Here, we recorded in vivo electrophysiological activity in the hippocampi of 16 mice, 8 of which had previously undergone a TBI. Consistent with previous data, we found that theta power in the hippocampus was decreased in TBI animals compared to sham controls; however, this effect was driven by changes in broadband power and not theta oscillations. This result suggests that broadband fluctuations in the hippocampal local field potential can be used as an electrophysiological surrogate of abnormal neurological activity post-TBI 6).