Brain energy metabolism: A roadmap for future research.

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.

Functional loss of ketogenesis in odontocete cetaceans.

Odontocete cetaceans exhibit genomic mutations in key ketogenesis genes. In order to validate an inferred lack of ketogenesis made by observations from genome sequencing, we biochemically analyzed tissues from several odontocete cetacean species and demonstrate that they indeed do not exhibit appreciable hepatic ß-hydroxybutyrate (ßHB) or its carnitine ester. Furthermore, liver tissue exhibited significantly lower long chain acylcarnitines and increased odd chain acylcarnitines indicative of a decreased reliance on hepatic long chain fatty acid oxidation in these carnivorous mammals. Finally, we performed single molecule, real-time next generation sequencing of liver and brain RNA of Tursiops truncatus and demonstrate that the succinyl-CoA transferase required for acetoacetate catabolism is expressed in the nervous system. These data show that odontocete cetaceans have lost the ability to perform ketogenesis and suggest a hepatocentric coenzyme A recycling function rather than a predominantly systemic-bioenergetic role for ketogenesis in other ketogenic competent mammals such as humans.

Intranasal epidermal growth factor treatment rescues neonatal brain injury.

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

Use of Telemedicine During Interhospital Transport of Children With Operative Intracranial Hemorrhage.

OBJECTIVES: To analyze the impact of an intervention of using telemedicine during interhospital transport on time to surgery in children with operative intracranial hemorrhage. DESIGN: We performed a retrospective chart review of children with intracranial hemorrhage transferred for emergent neurosurgical intervention between January 1, 2011 and December 31, 2016. We identified those patients whose neuroimaging was transmitted via telemedicine to the neurosurgical team prior to arrival at our center and then compared the telemedicine and nontelemedicine groups. Mann-Whitney U and Fisher exact tests were used to compare interval variables and categorical data. SETTING: Single-center study performed at Johns Hopkins Hospital. PATIENTS: Patients less than or equal to 18 years old transferred for operative intracranial hemorrhage. INTERVENTIONS: Pediatric transport implemented routine telemedicine use via departmental smart phones to facilitate transfer of information and imaging and reduce time to definitive care by having surgical services available when needed. MEASUREMENTS AND MAIN RESULTS: Fifteen children (eight in telemedicine group; seven in nontelemedicine group) met inclusion criteria. Most had extraaxial hemorrhage (87.5% telemedicine group; 85.7% nontelemedicine group; p = 1.0), were intubated pre transport (62.5% telemedicine group; 71.4% nontelemedicine group; p = 1.0), and arrived at our center's trauma bay during night shift or weekend (87.5% telemedicine group; 57.1% nontelemedicine group; p = 0.28). Median trauma bay Glasgow Coma Scale scores did not differ (eight in telemedicine group; seven in nontelemedicine group; p = 0.24). Although nonsignificant, when compared with the nontelemedicine group, the telemedicine group had decreased rates of repeat preoperative neuroimaging (37.5% vs 57%; p = 0.62), shorter median times from trauma bay arrival to surgery (33 min vs 47 min; p = 0.22) and from diagnosis to surgery (146.5 min vs 157 min; p = 0.45), shorter intensive care stay (2.5 vs 5 d) and hospitalization (4 vs 5 d), and higher home discharge rates (87.5% vs 57.1%; p = 0.28). CONCLUSIONS: Telemedicine use during interhospital transport appears to expedite definitive care for children with intracranial hemorrhage requiring emergent neurosurgical intervention, which could contribute to improved patient outcomes.

Developmental regulation and localization of carnitine palmitoyltransferases (CPTs) in rat brain.

While the brain's high energy demands are largely met by glucose, brain is also equipped with the ability to oxidize fatty acids for energy and metabolism. The brain expresses the carnitine palmitoyltransferases (CPTs) that mediate carnitine-dependent entry of long-chain acyl-CoAs into the mitochondrial matrix for ß-oxidation - CPT1a and CPT2 located on the outer and inner mitochondrial membranes, respectively. Their developmental profile, regional distribution and activity as well as cell type expression remain unknown. We determined that brain CPT1a RNA and total protein expression were unchanged throughout post-natal development (PND0, PND7, PND14, PND21 and PND50); however, CPT2 RNA peaked at PND 21 and remained unchanged through PND50 in all regions studied (cortex, hippocampus, midbrain, and cerebellum). Both long-chain acyl CoA dehydrogenase and medium acyl-CoA dehydrogenase showed a similar developmental profile to CPT2. Acylcarnitines, generated as a result of CPT1a activity, significantly increased with age and peaked at PND21 in all brain regions, concurrent with the increased expression of enzymes involved in mitochondrial ß-oxidation. The CPT system is highly enriched in vivo in hippocampus and cerebellum, relative to cortex and midbrain, and is exclusively present in astrocytes and neural progenitor cells, while absent in neurons, microglia, and oligodendrocytes. Using radiolabeled oleate, we demonstrate regional differences in brain fatty acid oxidation that may be blocked by the irreversible CPT1a inhibitor etomoxir. This study contributes to the field of knowledge in brain cell-specific metabolic pathways, which are important for understanding normal brain development and aging, as well as pathophysiology of neurological diseases. Read the Editorial Comment for this article on page 347.

Metabolic Alterations in Developing Brain After Injury: Knowns and Unknowns.

Brain development is a highly orchestrated complex process. The developing brain utilizes many substrates including glucose, ketone bodies, lactate, fatty acids and amino acids for energy, cell division and the biosynthesis of nucleotides, proteins and lipids. Metabolism is crucial to provide energy for all cellular processes required for brain development and function including ATP formation, synaptogenesis, synthesis, release and uptake of neurotransmitters, maintaining ionic gradients and redox status, and myelination. The rapidly growing population of infants and children with neurodevelopmental and cognitive impairments and life-long disability resulting from developmental brain injury is a significant public health concern. Brain injury in infants and children can have devastating effects because the injury is superimposed on the high metabolic demands of the developing brain. Acute injury in the pediatric brain can derail, halt or lead to dysregulation of the complex and highly regulated normal developmental processes. This paper provides a brief review of metabolism in developing brain and alterations found clinically and in animal models of developmental brain injury. The metabolic changes observed in three major categories of injury that can result in life-long cognitive and neurological disabilities, including neonatal hypoxia-ischemia, pediatric traumatic brain injury, and brain injury secondary to prematurity are reviewed.

A multicenter outcomes analysis of children with severe rhino/enteroviral respiratory infection.

OBJECTIVES: To investigate the impact of human rhino/enteroviruses on morbidity and mortality outcomes in children with severe viral respiratory infection. DESIGN: Retrospective cohort study. SETTING: The ICU, either PICU or cardiac ICU, at three urban academic tertiary-care children's hospitals. PATIENTS: All patients with laboratory-confirmed human rhino/enteroviruses infection between January 2010 and June 2011. INTERVENTIONS: We captured demographic and clinical data and analyzed associated morbidity and mortality outcomes. MEASUREMENTS AND MAIN RESULTS: There were 519 patients included in our analysis. The median patient age was 2.7 years. The median hospital and ICU lengths of stay were 4 days and 2 days, respectively. Thirty-four percent of patients had a history of asthma, and 25% of patients had a chronic medical condition other than asthma. Thirty-two percent of patients required mechanical ventilation. Eleven patients (2.1%) did not survive to hospital discharge. The rate of viral coinfection was 12.5% and was not associated with mortality. Predisposing factors associated with increased mortality included immunocompromised state (p < 0.001), ICU admission severity of illness score (p < 0.001), and bacterial coinfection (p = 0.003). CONCLUSIONS: There is substantial morbidity associated with severe respiratory infection due to human rhino/enteroviruses in children. Mortality was less severe than reported in other respiratory viruses such as influenza and respiratory syncytial virus. The burden of illness from human rhino/enteroviruses in the ICU in terms of resource utilization may be considerable.

Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model.

Cellular senescence, characterized by expressing the cell cycle inhibitory protein p21/CDKN1A, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D+Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), and structural MRI, and longitudinally assessed brain physiology and regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D+Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D+Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p21/CDKN1A. D+Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D+Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.

A multicenter outcomes analysis of children with severe viral respiratory infection due to human metapneumovirus.

OBJECTIVE: To investigate the impact of human metapneumovirus on morbidity and mortality outcomes in children with severe viral respiratory infection. DESIGN: Retrospective cohort study. SETTING: ICU, either PICU or cardiac ICU, at three urban academic tertiary care children's hospitals. PATIENTS: All patients admitted to an ICU with laboratory-confirmed human metapneumovirus infection between January 2010 and June 2011. INTERVENTIONS: We captured demographic and clinical data and analyzed associated morbidity and mortality outcomes. MEASUREMENTS AND MAIN RESULTS: There were 111 patients with laboratory-confirmed human metapneumovirus admitted to an ICU at one of the three participating institutions during the period of study. The median hospital length of stay was 7 days (interquartile range 4-18 days) and median ICU length of stay was 4 days (interquartile range 1-10 days). Ten patients (9%) did not survive to discharge. Predisposing factors associated with increased mortality included female gender (p = 0.002), presence of a chronic medical condition (p = 0.04), and hospital acquisition of human metapneumovirus infection (p = 0.006). Adjusting for female gender, chronic medical conditions, hospital acquisition of infection and severity of illness score, logistic regression analysis demonstrated that female gender, hospital acquisition of infection, and chronic medical conditions each independently increased the odds of mortality (odds ratios 14.8, 10.7, and 12.7, respectively). CONCLUSIONS: Analysis of our results suggests that there is substantial morbidity and mortality associated with severe viral respiratory infection due to human metapneumovirus in children. Female gender, hospital acquisition of human metapneumovirus infection, and presence of chronic medical conditions each independently increases mortality. The burden of illness from human metapneumovirus on the ICU in terms of resource utilization may be considerable.

Neonatal exposure to hypoxia induces early arterial stiffening via activation of lysyl oxidases.

Hypoxia in the neonatal period is associated with early manifestations of adverse cardiovascular health in adulthood including higher risk of hypertension and atherosclerosis. We hypothesize that this occurs due to activation of lysyl oxidases (LOXs) and the remodeling of the large conduit vessels, leading to early arterial stiffening. Newborn C57Bl/6 mice were exposed to hypoxia (FiO2  = 11.5%) from postnatal day 1 (P1) to postnatal day 11 (P11), followed by resumption of normoxia. Controls were maintained in normoxia. Using in vivo (pulse wave velocity; PWV) and ex vivo (tensile testing) arterial stiffness indexes, we determined that mice exposed to neonatal hypoxia had significantly higher arterial stiffness compared with normoxia controls by young adulthood (P60), and it increased further by P120. Echocardiography performed at P60 showed that mice exposed to hypoxia displayed a compensated dilated cardiomyopathy. Western blotting revelated that neonatal hypoxia accelerated age-related increase in LOXL2 protein expression in the aorta and elevated LOXL2 expression in the PA at P11 with a delayed decay toward normoxic controls. In the heart and lung, gene and protein expression of LOX/LOXL2 were upregulated at P11, with a delayed decay when compared to normoxic controls. Neonatal hypoxia results in a significant increase in arterial stiffness in early adulthood due to aberrant LOX/LOXL2 expression. This suggests an acceleration in the mechanical decline of the cardiovascular system, that contributes to increased risk of hypertension in young adults exposed to neonatal hypoxia that may increase susceptibility to further insults.

Perioperative Management of Pediatric Patients with Moyamoya Arteriopathy.

Pediatric patients with moyamoya arteriopathy are at high risk for developing new onset transient or permanent neurologic deficits secondary to cerebral hypoperfusion, particularly in the perioperative period. It is therefore essential to carefully manage these patients in a multidisciplinary, coordinated effort to reduce the risk of new permanent neurologic deficits. However, little has been published on perioperative management of pediatric patients with moyamoya, particularly in the early postoperative period during intensive care unit admission. Our pediatric neurocritical care team sought to create a multidisciplinary periprocedural evidence- and consensus-based care pathway for high-risk pediatric patients with moyamoya arteriopathy undergoing anesthesia for any reason to decrease the incidence of periprocedural stroke or transient ischemic attack (TIA). We reviewed the literature to identify risk factors associated with perioperative stroke or TIA among patients with moyamoya and to gather data supporting specific perioperative management strategies. A multidisciplinary team from pediatric anesthesia, neurocritical care, nursing, child life, neurosurgery, interventional neuroradiology, neurology, and hematology created a care pathway for children with moyamoya undergoing anesthesia, classifying them as either high or standard risk, and applying an individualized perioperative management plan to high-risk patients. The incidence of neurologic sequelae before and after pathway implementation will be compared in future studies.

Longitudinal in vivo developmental changes of metabolites in the hippocampus of Fmr1 knockout mice.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is studied in the Fmr1 knockout (KO) mouse, which models both the anatomical and behavioral changes observed in FXS patients. In vitro studies have shown many alterations in synaptic plasticity and increased density of immature dendritic spines in the hippocampus, a region involved in learning and memory. In this study, magnetic resonance imaging (MRI) and (1) H magnetic resonance spectroscopy (MRS) were used to determine in vivo longitudinal changes in volume and metabolites in the hippocampus during the critical period of early myelination and synaptogenesis at post-natal days (PND) 18, 21, and 30 in Fmr1 KO mice compared with wild-type (WT) controls. MRI demonstrated an increase in volume of the hippocampus in the Fmr1 KO mouse compared with controls. MRS revealed significant developmental changes in the ratios of hippocampal metabolites N-acetylaspartate (NAA), myo-inositol (Ins), and taurine to total creatine (tCr) in Fmr1 KO mice compared with WT controls. Ins was decreased at PND 30, and taurine was increased at all ages studied in Fmr1 KO mice compared with controls. An imbalance of brain metabolites in the hippocampus of Fmr1 KO mice during the critical developmental period of synaptogenesis and early myelination could have long-lasting effects that adversely affect brain development and contribute to ongoing alterations in brain function.

Metabolism of Exogenous [2,4-13C]ß-Hydroxybutyrate following Traumatic Brain Injury in 21-22-Day-Old Rats: An Ex Vivo NMR Study.

Traumatic brain injury (TBI) is leading cause of morbidity in young children. Acute dysregulation of oxidative glucose metabolism within the first hours after injury is a hallmark of TBI. The developing brain relies on ketones as well as glucose for energy. Thus, the aim of this study was to determine the metabolism of ketones early after TBI injury in the developing brain. Following the controlled cortical impact injury model of TBI, 21-22-day-old rats were infused with [2,4-13C]ß-hydroxybutyrate during the acute (4 h) period after injury. Using ex vivo 13C-NMR spectroscopy, we determined that 13C-ß-hydroxybutyrate (13C-BHB) metabolism was increased in both the ipsilateral and contralateral sides of the brain after TBI. Incorporation of the label was significantly higher in glutamate than glutamine, indicating that 13C-BHB metabolism was higher in neurons than astrocytes in both sham and injured brains. Our results show that (i) ketone metabolism was significantly higher in both the ipsilateral and contralateral sides of the injured brain after TBI; (ii) ketones were extensively metabolized by both astrocytes and neurons, albeit higher in neurons; (iii) the pyruvate recycling pathway determined by incorporation of the label from the metabolism of 13C-BHB into lactate was upregulated in the immature brain after TBI.

Brain water as a function of age and weight in normal rats.

Rats are frequently used for studying water content of normal and injured brain, as well as changes in response to various osmotherapeutic regimens. Magnetic resonance imaging in humans has shown that brain water content declines with age as a result of progressive myelination and other processes. The purpose of this study was to quantify changes in brain water content during rat development and aging. Brain water content was measured by standard techniques in 129 normal male Sprague-Dawley rats that ranged in age (weight) from 13 to 149 days (18 to 759 g). Overall, the results demonstrated a decrease in water content from 85.59% to 76.56% with increasing age (weight). Nonlinear allometric functions relating brain water to age and weight were determined. These findings provide age-related context for prior rat studies of brain water, emphasize the importance of using similarly aged controls in studies of brain water, and indicate that age-related changes in brain water content are not specific to humans.

Metabolism of acetyl-L-carnitine for energy and neurotransmitter synthesis in the immature rat brain.

Acetyl-L-carnitine (ALCAR) is an endogenous metabolic intermediate that facilitates the influx and efflux of acetyl groups across the mitochondrial inner membrane. Exogenously administered ALCAR has been used as a nutritional supplement and also as an experimental drug with reported neuroprotective properties and effects on brain metabolism. The aim of this study was to determine oxidative metabolism of ALCAR in the immature rat forebrain. Metabolism was studied in 21-22 day-old rat brain at 15, 60 and 120 min after an intraperitoneal injection of [2-(13)C]acetyl-L-carnitine. The amount, pattern, and fractional enrichment of (13)C-labeled metabolites were determined by ex vivo(13)C-NMR spectroscopy. Metabolism of the acetyl moiety from [2-(13)C]ALCAR via the tricarboxylic acid cycle led to incorporation of label into the C4, C3 and C2 positions of glutamate (GLU), glutamine (GLN) and GABA. Labeling patterns indicated that [2-(13)C]ALCAR was metabolized by both neurons and glia; however, the percent enrichment was higher in GLN and GABA than in GLU, demonstrating high metabolism in astrocytes and GABAergic neurons. Incorporation of label into the C3 position of alanine, both C3 and C2 positions of lactate, and the C1 and C5 positions of glutamate and glutamine demonstrated that [2-(13)C]ALCAR was actively metabolized via the pyruvate recycling pathway. The enrichment of metabolites with (13)C from metabolism of ALCAR was highest in alanine C3 (11%) and lactate C3 (10%), with considerable enrichment in GABA C4 (8%), GLN C3 (approximately 4%) and GLN C5 (5%). Overall, our (13)C-NMR studies reveal that the acetyl moiety of ALCAR is metabolized for energy in both astrocytes and neurons and the label incorporated into the neurotransmitters glutamate and GABA. Cycling ratios showed prolonged cycling of carbon from the acetyl moiety of ALCAR in the tricarboxylic acid cycle. Labeling of compounds formed from metabolism of [2-(13)C]ALCAR via the pyruvate recycling pathway was higher than values reported for other precursors and may reflect high activity of this pathway in the developing brain. This is, to our knowledge, the first study to determine the extent and pathways of ALCAR metabolism for energy and neurotransmitter biosynthesis in the brain.

Neuroprotection by acetyl-L-carnitine after traumatic injury to the immature rat brain.

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in children and is characterized by reduced aerobic cerebral energy metabolism early after injury, possibly due to impaired activity of the pyruvate dehydrogenase complex. Exogenous acetyl-L-carnitine (ALCAR) is metabolized in the brain to acetyl coenzyme A and subsequently enters the tricarboxylic acid cycle. ALCAR administration is neuroprotective in animal models of cerebral ischemia and spinal cord injury, but has not been tested for TBI. This study tested the hypothesis that treatment with ALCAR during the first 24 h following TBI in immature rats improves neurologic outcome and reduces cortical lesion volume. Postnatal day 21-22 male rats were isoflurane anesthetized and used in a controlled cortical impact model of TBI to the left parietal cortex. At 1, 4, 12 and 23 h after injury, rats received ALCAR (100 mg/kg, intraperitoneally) or drug vehicle (normal saline). On days 3-7 after surgery, behavior was assessed using beam walking and novel object recognition tests. On day 7, rats were transcardially perfused and brains were harvested for histological assessment of cortical lesion volume, using stereology. Injured animals displayed a significant increase in foot slips compared to sham-operated rats (6 ± 1 SEM vs. 2 ± 0.2 on day 3 after trauma; n = 7; p < 0.05). The ALCAR-treated rats were not different from shams and had fewer foot slips compared to vehicle-treated animals (2 ± 0.4; n = 7; p< 0.05). The frequency of investigating a novel object for saline-treated TBI animals was reduced compared to shams (45 ± 5% vs. 65 ± 10%; n = 7; p < 0.05), whereas the frequency of investigation for TBI rats treated with ALCAR was not significantly different from that of shams but significantly higher than that of saline-treated TBI rats (68 ± 7; p < 0.05). The left parietal cortical lesion volume, expressed as a percentage of the volume of tissue in the right hemisphere, was significantly smaller in ALCAR-treated than in vehicle-treated TBI rats (14 ± 5% vs. 28 ± 6%; p < 0.05). We conclude that treatment with ALCAR during the first 24 h after TBI improves behavioral outcomes and reduces brain lesion volume in immature rats within the first 7 days after injury.

Microglial Metabolism After Pediatric Traumatic Brain Injury - Overlooked Bystanders or Active Participants?

Microglia play an integral role in brain development but are also crucial for repair and recovery after traumatic brain injury (TBI). TBI induces an intense innate immune response in the immature, developing brain that is associated with acute and chronic changes in microglial function. These changes contribute to long-lasting consequences on development, neurologic function, and behavior. Although alterations in glucose metabolism are well-described after TBI, the bulk of the data is focused on metabolic alterations in astrocytes and neurons. To date, the interplay between alterations in intracellular metabolic pathways in microglia and the innate immune response in the brain following an injury is not well-studied. In this review, we broadly discuss the microglial responses after TBI. In addition, we highlight reported metabolic alterations in microglia and macrophages, and provide perspective on how changes in glucose, fatty acid, and amino acid metabolism can influence and modulate the microglial phenotype and response to injury.

Evaluation and Management of Symptomatic Vasospasm following Endoscopic Endonasal Resection of Pediatric Adamantinomatous Craniopharyngioma.

BACKGROUND: Cerebral vasospasm is a well-described pathology following subarachnoid hemorrhage and trauma in children; however, very few cases have been published following craniopharyngioma resection in children. Those that were published were associated with significant morbidity or mortality at hospital discharge. Case Summary. Here, we report the challenging clinical course of a pediatric patient who developed delayed cerebral vasospasm following craniopharyngioma resection. It was first noted on postoperative day 13. The patient was managed with induced hypertension, hypervolemia, and intra-arterial vasodilator therapy (nicardipine). This patient made a full recovery without new focal deficits at hospital discharge. CONCLUSION: In contrast to previously reported similar pediatric cases, this patient with cerebral vasospasm after craniopharyngioma resection made a full recovery without new focal neurologic deficits. To our knowledge, this is the first occurrence of a patient with this clinical course.

Determining the Bioenergetic Capacity for Fatty Acid Oxidation in the Mammalian Nervous System.

The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid ß-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2B-/-). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids in vitro and in vivo Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.