Thomas C. Glenn

Traumatic brain injury (TBI) is an expanding public health epidemic with pathophysiology that is difficult to diagnose and thus treat. TBI biomarkers should assess patients across severities and reveal pathophysiology, but currently, their kinetics and specificity are unclear. No single ideal TBI biomarker exists. We identified new candidates from a TBI CSF proteome by selecting trauma-released, astrocyte-enriched proteins including aldolase C (ALDOC), its 38kD breakdown product (BDP), brain lipid binding protein (BLBP), astrocytic phosphoprotein (PEA15), glutamine synthetase (GS) and new 18-25kD-GFAP-BDPs. Their levels increased over four orders of magnitude in severe TBI CSF. First post-injury week, ALDOC levels were markedly high and stable. Short-lived BLBP and PEA15 related to injury progression. ALDOC, BLBP and PEA15 appeared hyper-acutely and were similarly robust in severe and mild TBI blood; 25kD-GFAP-BDP appeared overnight after TBI and was rarely present after mild TBI. Using a human culture trauma model, we investigated biomarker kinetics. Wounded (mechanoporated) astrocytes released ALDOC, BLBP and PEA15 acutely. Delayed cell death corresponded with GFAP release and proteolysis into small GFAP-BDPs. Associating biomarkers with cellular injury stages produced astroglial injury-defined (AID) biomarkers that facilitate TBI assessment, as neurological deficits are rooted not only in death of CNS cells, but also in their functional compromise.

Traumatic brain injury (TBI) is associated with acute cerebral metabolic crisis (ACMC). ACMC‐related atrophy appears to be prominent in frontal and temporal lobes following moderate‐to‐severe TBI. This atrophy is correlated with poorer cognitive outcomes in TBI. The current study investigated ability of acute glucose and lactate metabolism to predict long‐term recovery of frontal‐temporal cognitive function in participants with moderate‐to‐severe TBI. Cerebral metabolic rate of glucose and lactate were measured by the Kety‐Schmidt method on days 0–7 post‐injury. Indices of frontal‐temporal cognitive processing were calculated for six months post‐injury; 12 months post‐injury; and recovery (the difference between the six‐ and 12‐month scores). Glucose and lactate metabolism were included in separate regression models, as they were highly intercorrelated. Also, glucose and lactate values were centered and averaged and included in a final regression model. Models for the prediction frontal‐temporal cognition at six and 12 months post‐injury were not significant. However, average glucose and lactate metabolism predicted recovery of frontal‐temporal cognition, accounting for 23% and 22% of the variance, respectively. Also, maximum glucose metabolism, but not maximum lactate metabolism, was an inverse predictor in the recovery of frontal‐temporal cognition, accounting for 23% of the variance. Finally, the average of glucose and lactate metabolism predicted frontal‐temporal cognitive recovery, accounting for 22% of the variance. These data indicate that acute glucose and lactate metabolism both support cognitive recovery from TBI. Also, our data suggest that control of endogenous fuels and/or supplementation with exogenous fuels may have therapeutic potential for cognitive recovery from TBI.

Background The objective was to investigate the impact of targeting tight glycemic control (4.4–6.1 mM) on endogenous ketogenesis in severely head-injured adults. Methods The data were prospectively collected during a randomized, within-patient crossover study comparing tight to loose glycemic control, defined as 6.7–8.3 mM. Blood was collected periodically during both tight and loose glycemic control epochs. Post hoc analysis of insulin dose and total nutritional provision was performed. Results Fifteen patients completed the crossover study. Total ketones were increased 81 μM ([38 135], p < 0.001) when blood glucose was targeted to tight (4.4–6.1 mM) compared with loose glycemic control (6.7–8.3 mM), corresponding to a 60 % increase. There was a significant decrease in total nutritional provisions (p = 0.006) and a significant increase in insulin dose (p = 0.008). Conclusions Permissive underfeeding was tolerated when targeting tight glycemic control, but total nutritional support is an important factor when treating hyperglycemia.

Cerebral metabolism of ketones after traumatic brain injury (TBI) improves neuropathology and behavior in an age-dependent manner. Neuroprotection is attributed to improved cellular energetics, although other properties contribute to the beneficial effects. Oxidative stress is responsible for mitochondrial dysfunction after TBI. Ketones decrease oxidative stress, increase antioxidants and scavenge free radicals. It is hypothesized that ketogenic diet (KD) will decrease post-TBI oxidative stress and improve mitochondria. Postnatal day 35 (PND35) male rats were given sham or controlled cortical impact (CCI) injury and placed on standard (STD) or KD. Ipsilateral cortex homogenates and mitochondria were assayed for markers of oxidative stress, antioxidant expression and mitochondrial function. Oxidative stress was significantly increased at 6 and 24 h post-injury and attenuated by KD while inducing protein expression of antioxidants, NAD(P)H dehydrogenase quinone 1 (NQO1) and superoxide dismutase (SOD1/2). Complex I activity was inhibited in STD and KD groups at 6 h and normalized by 24 h. KD significantly improved Complex II–III activity that was reduced in STD at 6 h. Activity remained reduced at 24 h in STD and unchanged in KD animals. These results strongly suggest that ketones improve post-TBI cerebral metabolism by providing alternative substrates and through antioxidant properties, preventing oxidative stress-mediated mitochondrial dysfunction.

We evaluated the hypothesis that lactate shuttling helps support the nutritive needs of injured brains. To that end, we utilized dual isotope tracer [6,6- ² H2]glucose, that is, D2-glucose, and [3- ¹³ C]lactate techniques involving arm vein tracer infusion along with simultaneous cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Traumatic brain injury (TBI) patients with nonpenetrating brain injuries ( n =12) were entered into the study following consent of patients' legal representatives. Written and informed consent was obtained from control volunteers ( n =6). Patients were studied 5.7±2.2 (mean±SD) days post-injury; during periods when arterial glucose concentration tended to be higher in TBI patients. As in previous investigations, the cerebral metabolic rate for glucose (CMRgluc, i.e., net glucose uptake) was significantly suppressed following TBI ( p 13 CO ₂ into the JB accounted for 92% and 91% for control and TBI conditions, respectively, suggesting that most cerebral lactate uptake was oxidized following TBI. Comparisons of isotopic enrichments of lactate oxidation from infused [3- ¹³ C]lactate tracer and ¹³ C-glucose produced during hepatic and renal gluconeogenesis (GNG) showed that 75–80% of ¹³ CO ₂ released into the JB was from lactate and that the remainder was from the oxidation of glucose secondarily labeled from lactate. Hence, either directly as lactate uptake, or indirectly via GNG, peripheral lactate production accounted for ∼70% of carbohydrate (direct lactate uptake+uptake of glucose from lactate) consumed by the injured brain. Undiminished cerebral lactate fractional extraction and uptake suggest that arterial lactate supplementation may be used to compensate for decreased CMRgluc following TBI.

We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6- ² H2]glucose, i.e., D ₂ -glucose, and [3- ¹³ C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries ( n =12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls ( n =6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2–10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain.

Primary objective: The aim of this literature review was to systematically describe the sequential metabolic changes that occur following concussive injury, as well as identify and characterize the major concepts associated with the neurochemical cascade. Research design: Narrative literature review. Conclusions: Concussive injury initiates a complex cascade of pathophysiological changes that include hyper-acute ionic flux, indiscriminant excitatory neurotransmitter release, acute hyperglycolysis and sub-acute metabolic depression. Additionally, these metabolic changes can subsequently lead to impaired neurotransmission, alternate fuel usage and modifications in synaptic plasticity and protein expression. The combination of these metabolic alterations has been proposed to cause the transient and prolonged neurological deficits that typically characterize concussion. Consequently, understanding the implications of the neurochemical cascade may lead to treatment and return-to-play guidelines that can minimize the chronic effects of concussive injury.

Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as ‘frontal-temporal’ in nature, suggesting a possible link between acute metabolic crisis-related brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis-related brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis‐related atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors.