Negev, Shahar

Background: Diffuse axonal brain injury (DABI) is a major component of traumatic brain injury, but the optimal timing of magnetic resonance imaging and histologic assessment after isolated DABI remains unclear. Because each method captures a different phase of injury, defining time-dependent diagnostic windows may improve experimental design and reduce animal use. Methods: Sixty-four Sprague-Dawley rats were randomized to moderate DABI or sham operation. Neurological Severity Score (NSS), 3 T diffusion tensor imaging (DTI), and histologic assessment were performed at early and late time points. Hippocampal fractional anisotropy (FA) was measured at 48 h and 1 month. β-amyloid precursor protein (β-APP) immunohistochemistry assessed acute axonal injury at 48 h, and hematoxylin and eosin (H&E) staining quantified hippocampal neuronal density at 1 month. Results: At 48 h, DABI rats had higher NSS, lower hippocampal FA, and greater β-APP-positive axonal accumulation than sham-operated rats. By 1 month, NSS and hippocampal FA no longer differed between groups, whereas hippocampal neuronal density remained significantly reduced in DABI rats, indicating persistent structural injury. Conclusions: In this rat model of isolated DABI, hippocampal FA and β-APP immunohistochemistry identified acute axonal pathology at 48 h, whereas conventional histology detected a persistent reduction in neuronal density at 1 month. These findings support a time-optimized diagnostic strategy using early DTI for noninvasive injury detection and late histology for long-term structural assessment.

Delirium is a serious neuropsychiatric condition marked by acute confusion and cognitive decline, commonly affecting postoperative and critically ill patients. It is especially prevalent in older adults and those requiring intensive care, including patients undergoing major surgery or receiving mechanical ventilation. For anesthesiologists, delirium is a critical and often underrecognized postoperative complication with complex perioperative contributors. Intensive care unit patients with delirium face increased mortality, cognitive impairment, and persistent symptoms beyond discharge. Despite its clinical significance, the pathophysiology of delirium remains poorly understood, with no standardized classification or targeted therapy. In light of emerging evidence connecting blood–brain barrier (BBB) permeability to the onset of delirium, we found that BBB dysfunction may represent a key mechanism underlying its pathophysiology. Through a thorough examination of predisposing and precipitating factors that impair both BBB integrity and cognitive function, we identified many points of connection between BBB dysfunction and delirium specifically. We include here a summary of our diagnostic approach with the aim of improving therapeutic strategies based on preserving BBB function to prevent or mitigate delirium.

Diffuse axonal brain injury (DAI) is a common, debilitating consequence of traumatic brain injury, yet its detection and severity grading remain challenging in clinical and experimental settings. This study evaluated the sensitivity of diffusion tensor imaging (DTI), histology, and neurological severity scoring (NSS) in assessing injury severity in a rat model of isolated DAI. A rotational injury model induced mild, moderate, or severe DAI in male and female rats. Neurological deficits were assessed 48 h after injury via NSS. Magnetic resonance imaging, including DTI metrics, such as fractional anisotropy (FA), relative anisotropy (RA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD), was performed prior to tissue collection. Histological analysis used beta amyloid precursor protein immunohistochemistry. Sensitivity and variability of each method were compared across brain regions and the whole brain. Histology was the most sensitive method, requiring very small groups to detect differences. Anisotropy-based MRI metrics, especially whole-brain FA and RA, showed strong correlations with histology and NSS and demonstrated high sensitivity with low variability. NSS identified injury but required larger group sizes. Diffusivity-based MRI metrics, particularly RD, were less sensitive and more variable. Whole-brain FA and RA were the most sensitive MRI measures of DAI severity and were comparable to histology in moderate and severe groups. These findings support combining NSS and anisotropy-based DTI for non-terminal DAI assessment in preclinical studies.

Traumatic brain injury (TBI), a major cause of death and disability among young people, leads to significant public health and economic challenges. Despite its frequency, treatment options remain largely unsuitable. However, examination of the blood–brain barrier (BBB) can assist with understanding the mechanisms and dynamics of brain dysfunction, which affects TBI sufferers secondarily to the injury. Here, we present a rat model of TBI focused on two standard BBB assessment markers, high- and low-molecular-weight complexes, in order to understand BBB disruption. In addition, we tested a new technique to evaluate BBB disruption on a single brain set, comparing the new technique with neuroimaging. A total of 100 Sprague–Dawley rats were separated into the following five groups: naive rats (n = 20 rats), control rats with administration (n = 20 rats), and TBI rats (n = 60 rats). Rats were assessed at different time points after the injury to measure BBB disruption using low- and high-molecular-weight complexes. Neurological severity score was evaluated at baseline and at 24 h following TBI. During the neurological exam after TBI, the rats were scanned with magnetic resonance imaging and euthanized for assessment of the BBB permeability. We found that the two markers displayed different examples of BBB disruption in the same set of brain tissues over the period of a week. Our innovative protocol for assessing BBB permeability using high- and low-molecular-weight complexes markers in a single brain set showed appropriate results. Additionally, we determined the lower limit of sensitivity, therefore demonstrating the accuracy of this method.

A healthy blood–brain barrier (BBB) shields the brain from high concentrations of blood glutamate, which can cause neurotoxicity and neurodegeneration. It is believed that traumatic brain injury (TBI) causes long-term BBB disruption, subsequently increasing brain glutamate in the blood, in addition to increased glutamate resulting from the neuronal injury. Here, we investigate the relationship between blood and brain glutamate levels in the context of BBB permeability. Rats exposed to BBB disruption through an osmotic model or TBI and treated with intravenous glutamate or saline were compared to control rats with an intact BBB treated with intravenous glutamate or saline. After BBB disruption and glutamate administration, the concentrations of glutamate in the cerebrospinal fluid and blood and brain tissue were analyzed. The results showed a strong correlation between the brain and blood glutamate concentrations in the groups with BBB disruption. We conclude that a healthy BBB protects the brain from high levels of blood glutamate, and the permeability of the BBB is a vital component in regulating levels of glutamate in the brain. These findings bring a new approach to treating the consequences of TBI and other diseases where long-term disruption of the BBB is the central mechanism of their development.