Sandra Magnoni

Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain

The amyloid-β peptide (Aβ) plays a central pathophysiological role in Alzheimers disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Aβ concentrations and neurological status, with Aβ concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Aβ concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentration.

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury

Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100 kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P = 0.005). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.6, P = 0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P = 0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-β levels measured in the same samples (r = -0.87, P = 0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-β release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r = -0.6, P = 0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach provides added value when combined with clinical and radiological information.

Impact of pyrexia on neurochemistry and cerebral oxygenation after acute brain injury.

Background: Postischaemic pyrexia exacerbates neuronal damage. Hyperthermia related cerebral changes have still not been well investigated in humans. Objective: To study how pyrexia affects neurochemistry and cerebral oxygenation after acute brain injury. Methods: 18 acutely brain injured patients were studied at the onset and resolution of febrile episodes (brain temperature ⩾38.7°C). Intracranial pressure (ICP), brain tissue oxygen tension (Pbro2), and brain tissue temperature (Tbr) were recorded continuously; jugular venous blood was sampled intermittently. Microdialysis probes were inserted in the cerebral cortex and in subcutaneous tissue. Glucose, lactate, pyruvate, and glutamate were measured hourly. The lactate to pyruvate ratio was calculated. Results: Mean (SD) Tbr rose from 38 (0.5) to 39.3 (0.3)°C. Arteriojugular oxygen content difference (AJDo2) fell from 4.2 (0.7) to 3.8 (0.5) vol% (p<0.05) and Pbro2 rose from 32 (21) to 37 (22) mm Hg (p<0.05). ICP increased slightly and no significant neurochemical alterations occurred. Opposite changes were recorded when brain temperature returned towards baseline. Conclusions: As long as substrate and oxygen delivery remain adequate, hyperthermia on its own does not seem to induce any further significant neurochemical alterations. Changes in cerebral blood volume may, however, affect intracranial pressure.

New Perspectives on Amyloid-β Dynamics After Acute Brain Injury: Moving Between Experimental Approaches and Studies in the Human Brain

The links between traumatic brain injury and Alzheimer disease have been of great interest for many years. However, the importance of amyloid-β-related neurodegenerative pathophysiologic processes after traumatic brain injury is still unknown. In this review, we present a brief overview of the scientific evidence regarding traumatic brain injury as a contributor to Alzheimer disease and describe recent results showing significant changes in brain extracellular amyloid-β dynamics in patients with severe brain injury. We then discuss the clinical significance of these findings with their implications for translational neurobiology and conclude with further directions for traumatic brain injury and Alzheimer disease research.

Arterio-jugular Difference of Oxygen Content and Outcome After Head Injury

This study investigated AJDo2 (arterio-jugular difference of oxygen content) in a large sample of severely head-injured patients to identify its pattern during the first days after injury and to describe the relationship of AJDo2 with acute neurological severity and with outcome 6 mo after trauma. In 229 comatose head-injured patients, we monitored intracranial pressure, cerebral perfusion pressure, and AJDo2. Outcome was defined 6 mo after injury. Jugular hemoglobin oxygen saturation (Sjo2) averaged 68%. The mean AJDo2 was 4.24 vol% (sd, 1.3 vol%). There were 80 measurements (4.6%) with Sjo2 <5% and 304 (17.6%) with saturation >75%. AJDo2 was higher than 8.7 vol% in 8 measurements (0.4%) and was lower than 3.9 vol% in 718 (42%) measurements. AJDo2 was higher during the first tests and decreased steadily over the next few days. Cases with a favorable outcome had a higher mean AJDo2 (4.3 vol%; sd, 0.3 vol%) than patients with severe disability or vegetative status (3.8 vol%; sd, 1.3 vol%) and patients who died (3.6 vol%; sd, 1 vol%). This difference was significant (P < 0.001). We conclude that low levels of AJDo2 are correlated with a poor prognosis, whereas normal or high levels of AJDo2 are predictive of better results.

α-Melanocyte-Stimulating Hormone Is Decreased in Plasma of Patients with Acute Brain Injury

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a proopiomelanocortin derivative that has potent anti-inflammatory influences within the brain. The aim of the present research was to d...

Relationship between systemic glucose and cerebral glucose is preserved in patients with severe traumatic brain injury, but glucose delivery to the brain may become limited when oxidative metabolism is impaired: implications for glycemic control.

Objective:To clarify the dynamics of glucose delivery to the brain and the effects of changes in blood glucose after severe traumatic brain injury. Design:Retrospective analysis of a prospective observational cohort study. Setting:Neurosurgical intensive care unit of a university hospital. Patients:Seventeen patients with acute traumatic brain injury monitored with cerebral and subcutaneous microdialysis. Interventions:None. Measurements and Main Results:For continuous, accurate systemic monitoring, glucose was measured in the interstitial space of subcutaneous adipose tissue using microdialysis, and 39 specific episodes of spontaneous rises in glucose were identified. During these episodes, there was a significant positive linear relationship between systemic glucose levels and brain glucose concentrations measured by microdialysis (p < .0001). The basal lactate/pyruvate ratio, with a threshold of 25, was adopted to distinguish between disturbed and presumably preserved cerebral oxidative metabolism. Using normal vs. elevated lactate/pyruvate ratio as variable factor, the relationship between brain and systemic glucose during the episodes could be described by two significantly distinct parallel lines (p = .0001), which indicates a strong additive effect of subcutaneous glucose and lactate/pyruvate ratio in determining brain glucose. The line describing the relationship under disturbed metabolic conditions was lower than in presumably intact metabolic conditions, with a significant difference of 0.648 ± 0.192 mM (p = .002). This let us to accurately predict that in this situation systemic glucose concentrations in the lower range of normality would result in critical brain glucose levels. Conclusions:The linear relationship between systemic and brain glucose in healthy subjects is preserved in traumatic brain-injured patients. As a consequence, in brain tissue where oxidative metabolism is disturbed, brain glucose concentrations might possibly drop below the critical threshold of 0.8 mM to 1.0 mM when there is a reduction in systemic glucose toward the lower limits of the “normal” range.

Quantitative assessments of traumatic axonal injury in human brain: concordance of microdialysis and advanced MRI

Axonal injury is a major contributor to adverse outcomes following brain trauma. However, the extent of axonal injury cannot currently be assessed reliably in living humans. Here, we used two experimental methods with distinct noise sources and limitations in the same cohort of 15 patients with severe traumatic brain injury to assess axonal injury. One hundred kilodalton cut-off microdialysis catheters were implanted at a median time of 17 h (13-29 h) after injury in normal appearing (on computed tomography scan) frontal white matter in all patients, and samples were collected for at least 72 h. Multiple analytes, such as the metabolic markers glucose, lactate, pyruvate, glutamate and tau and amyloid-β proteins, were measured every 1-2 h in the microdialysis samples. Diffusion tensor magnetic resonance imaging scans at 3 T were performed 2-9 weeks after injury in 11 patients. Stability of diffusion tensor imaging findings was verified by repeat scans 1-3 years later in seven patients. An additional four patients were scanned only at 1-3 years after injury. Imaging abnormalities were assessed based on comparisons with five healthy control subjects for each patient, matched by age and sex (32 controls in total). No safety concerns arose during either microdialysis or scanning. We found that acute microdialysis measurements of the axonal cytoskeletal protein tau in the brain extracellular space correlated well with diffusion tensor magnetic resonance imaging-based measurements of reduced brain white matter integrity in the 1-cm radius white matter-masked region near the microdialysis catheter insertion sites. Specifically, we found a significant inverse correlation between microdialysis measured levels of tau 13-36 h after injury and anisotropy reductions in comparison with healthy controls (Spearmans r = -0.64, P = 0.006). Anisotropy reductions near microdialysis catheter insertion sites were highly correlated with reductions in multiple additional white matter regions. We interpret this result to mean that both microdialysis and diffusion tensor magnetic resonance imaging accurately reflect the same pathophysiological process: traumatic axonal injury. This cross-validation increases confidence in both methods for the clinical assessment of axonal injury. However, neither microdialysis nor diffusion tensor magnetic resonance imaging have been validated versus post-mortem histology in humans. Furthermore, future work will be required to determine the prognostic significance of these assessments of traumatic axonal injury when combined with other clinical and radiological measures.

Analysis of propofol/remifentanil infusion protocol for tumor surgery with intraoperative brain mapping.

Background There is no general consensus about the best anesthesiologic approach to use during craniotomies with intraoperative brain mapping, and large prospective studies evaluating the complications associated with different approaches are lacking. Objective of this study was to prospectively collect and evaluate data about a large series of consecutive asleep-awake and asleep-asleep craniotomies. Methods We analyzed 238 consecutive procedures from January 2005 to December 2008. During asleep-awake procedures, patients were initially ventilated through a laryngeal mask which was removed to allow language testing. During asleep-asleep procedures, patients remained sedated and intubated to permit motor testing. Results In asleep-awake craniotomies [n=135, age 42 y (range: 16 to 72 y), American Society of Anesthologists classification (ASA) 1 (1 to 3), and body mass index 24.2±3.7 kg/m2], 43% of the procedures were free of complications. Most common complications were hypertension (27%) and brief clinical seizures (16%), but also hypotension (10%), vomiting (7%), brief periods of apnea (4%), and agitation (6%) were observed. In 7% of the procedures, seizures required pharmacologic treatment. Fifty-nine percent of the asleep-asleep procedures [n=103, age 51 y (range: 21 to 76 y), ASA 1 (1 to 3), body mass index 25.4±3.9 kg/m2, P<0.05 vs. asleep-awake] were free of complications. Clinical seizures were observed in 31% of the cases. The administration of boluses of hypnotics was rarely necessary (6%) and safer because of secured airways. Conclusions With this study, we demonstrated the feasibility and safety of our protocols on large prospective case series. Asleep-awake protocol can be safely used when intraoperative language mapping is planned, whereas an asleep-asleep protocol with secured airway might be preferred when motor testing only is required.

Experimental subarachnoid haemorrhage results in multifocal axonal injury

The great majority of acute brain injury results from trauma or from disorders of the cerebrovasculature, i.e. ischaemic stroke or haemorrhage. These injuries are characterized by an initial insult that triggers a cascade of injurious cellular processes. The nature of these processes in spontaneous intracranial haemorrhage is poorly understood. Subarachnoid haemorrhage, a particularly deadly form of intracranial haemorrhage, shares key pathophysiological features with traumatic brain injury including exposure to a sudden pressure pulse. Here we provide evidence that axonal injury, a signature characteristic of traumatic brain injury, is also a prominent feature of experimental subarachnoid haemorrhage. Using histological markers of membrane disruption and cytoskeletal injury validated in analyses of traumatic brain injury, we show that axonal injury also occurs following subarachnoid haemorrhage in an animal model. Consistent with the higher prevalence of global as opposed to focal deficits after subarachnoid haemorrhage and traumatic brain injury in humans, axonal injury in this model is observed in a multifocal pattern not limited to the immediate vicinity of the ruptured artery. Ultrastructural analysis further reveals characteristic axonal membrane and cytoskeletal changes similar to those associated with traumatic axonal injury. Diffusion tensor imaging, a translational imaging technique previously validated in traumatic axonal injury, from these same specimens demonstrates decrements in anisotropy that correlate with histological axonal injury and functional outcomes. These radiological indicators identify a fibre orientation-dependent gradient of axonal injury consistent with a barotraumatic mechanism. Although traumatic and haemorrhagic acute brain injury are generally considered separately, these data suggest that a signature pathology of traumatic brain injury-axonal injury-is also a functionally significant feature of subarachnoid haemorrhage, raising the prospect of common diagnostic, prognostic, and therapeutic approaches to these conditions.