Persistent metabolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts chronic frontal lobe brain atrophy after traumatic brain injury*

Marcoux, Judith; McArthur, D.A.; Miller, Chad M.; Glenn, Thomas C.; Villablanca, Pablo; Martin, Neil A.; Hovda, David A.; Alger, Jeffry R.; Vespa, Paul

doi:10.1097/ccm.0b013e318186a4a0

Cited by 143 publications

(86 citation statements)

References 24 publications

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“…It results in immediate cellular death in a limited region of the brain directly involved in the insult, usually a brain contusion, while creating a more widespread state of metabolic dysfunction in remote areas of the brain (Feeney and Baron, 1986). Secondary cell loss takes the form of chronic diffuse atrophy in regions not directly involved in the primary injury or adjacent to the primary contusion (Marcoux et al, 2008). Chronic brain atrophy has been correlated with poor neurologic outcome (Sidaros et al, 2009) and seems to be progressive over a period ranging from months to years after the injury.…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms involved in this chronic atrophy have not been well studied. In an initial study (Marcoux et al, 2008), our group at UCLA (University of California at Los Angeles) evaluated the role of early metabolic dysfunction on subsequent brain atrophy. The principal finding was that the duration of persistent metabolic crisis as measured by the elevated lactatepyruvate ratio is associated with the extent of regional frontal lobe atrophy.…”

Section: Introductionmentioning

confidence: 99%

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Early Nonischemic Oxidative Metabolic Dysfunction Leads to Chronic Brain Atrophy in Traumatic Brain Injury

McArthur

Alger

et al. 2009

J Cereb Blood Flow Metab

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Chronic brain atrophy after traumatic brain injury (TBI) is a well-known phenomenon, the causes of which are unknown. Early nonischemic reduction in oxidative metabolism is regionally associated with chronic brain atrophy after TBI. A total of 32 patients with moderate-to-severe TBI prospectively underwent positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) within the first week and at 6 months after injury. Regional lobar assessments comprised oxidative metabolism and glucose metabolism. Acute MRI showed a preponderance of hemorrhagic lesions with few irreversible ischemic lesions. Global and regional chronic brain atrophy occurred in all patients by 6 months, with the temporal and frontal lobes exhibiting the most atrophy compared with the occipital lobe. Global and regional reduction in cerebral metabolic rate of oxygen (CMRO 2 ), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose were observed. The extent of metabolic dysfunction was correlated with the total hemorrhage burden on initial MRI (r = 0.62, P = 0.01). The extent of regional brain atrophy correlated best with CMRO 2 and CBF. Lobar values of OEF were not in the ischemic range and did not correlate with chronic brain atrophy. Chronic brain atrophy is regionally specific and associated with regional reductions in oxidative brain metabolism in the absence of irreversible ischemia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early Nonischemic Oxidative Metabolic Dysfunction Leads to Chronic Brain Atrophy in Traumatic Brain Injury

McArthur

Alger

et al. 2009

J Cereb Blood Flow Metab

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“…20 A non-ischemic metabolic crisis occurs frequently after TBI, and abnormal biomarker levels predictive of poor outcome are the following: LPR 440, lactate 41.5 mmol/L, glucose o 0.2 mmol/L, pyruvate o25 μmol/L, glutamate 45 μmol/L, and glycerol 450 μmol/L, with a negative correlation between the global rate of oxygen consumption (CMR O2 ) and microdialysate LPR. 8,19,21 A nonischemic rise in LPR above the normal range of 20 to 25 due mainly to low pyruvate is classified as type 2 LPR (contrasting type 1 LPR, associated with ischemia, high lactate, and low pyruvate), suggesting a hyperglycolytic state in which glucose demand exceeds supply, glycolysis may be impaired, glucose may be diverted to other pathways, and mitochondria are dysfunctional; metabolic crisis with normal oxygen and pyruvate levels suggests an increased rate of glucose utilization (CMR glc ) via glycolysis, sufficient glucose supply, and mitochondrial dysfunction. 9,17,18,22 In contrast, major metabolic features of activation in normal brain include glucose supply matches increased demand, oxygen delivery exceeds demand, CMR glc 4 CMR O2 , lactate and pyruvate levels increase in parallel, LPR is normal, and lactate is released in blood.…”

Section: Injury Classificationmentioning

confidence: 99%

“…6 Poor outcome after TBI is associated with low oxygen, glucose, pyruvate levels, high LPR, and elevated glutamate and glycerol levels, particularly when changes have longer duration and higher magnitude. [7][8][9][10] Probe Site Microdialysis catheter location is important, e.g., in gray or white matter ipsilateral or contralateral to the injury because metabolite level changes are larger in lesioned or penumbral zones compared with distant 'normal' tissue. [10][11][12] Also, gray and white matter exhibit different magnitudes and time courses of responses (i) to hypoxia for lactate and pyruvate in immature brain, 13 and (ii) to ischemia and reperfusion for the decline in direct current potential and levels of extracellular [Ca 2+ ], adenosine, inosine, hypoxanthine, glutamate, and GABA in adult brain, with white matter being usually less negatively affected.…”

Section: Brain Microdialysis After Traumatic Brain Injurymentioning

confidence: 99%

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

Dienel

2014

J Cereb Blood Flow Metab

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Lactate is proposed to be generated by astrocytes during glutamatergic neurotransmission and shuttled to neurons as 'preferred' oxidative fuel. However, a large body of evidence demonstrates that metabolic changes during activation of living brain disprove essential components of the astrocyte-neuron lactate shuttle model. For example, some glutamate is oxidized to generate ATP after its uptake into astrocytes and neuronal glucose phosphorylation rises during activation and provides pyruvate for oxidation. Extension of the notion that lactate is a preferential fuel into the traumatic brain injury (TBI) field has important clinical implications, and the concept must, therefore, be carefully evaluated before implementation into patient care. Microdialysis studies in TBI patients demonstrate that lactate and pyruvate levels and lactate/pyruvate ratios, along with other data, have important diagnostic value to distinguish between ischemia and mitochondrial dysfunction. Results show that lactate release from human brain to blood predominates over its uptake after TBI, and strong evidence for lactate metabolism is lacking; mitochondrial dysfunction may inhibit lactate oxidation. Claims that exogenous lactate infusion is energetically beneficial for TBI patients are not based on metabolic assays and data are incorrectly interpreted.

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“…23,24 Although the impact on clinical outcome was not the primary purpose of this study, numerous studies have established a close correlation between cerebral metabolism and clinical outcome. 3,25,26 These preliminary results provide the rationale for a larger scale study for investigation of the potential clinical benefit of this appealing drug.…”

Section: Mitochondrial Permeability Transitionmentioning

confidence: 99%

Mitochondrial Damage: A Target for New Therapeutic Horizons

Soustiel

Larisch

2010

Neurotherapeutics

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Summary: Traumatic brain injury (TBI) represents a leading cause of death and morbidity, as well as a considerable social and economical burden in western countries, and has thus emerged as a formidable therapeutic challenge. Yet despite tremendous efforts enlightening the mechanisms of neuronal death, hopes for the "magic bullet" have been repeatedly deceived, and TBI management has remained focused on the control of increased intracranial pressure. Indeed, impairment of cerebral metabolism is traditionally attributed to impaired oxygen delivery mediated by reduced cerebral perfusion in the swollen cerebral parenchyma. Although intuitively appealing, this hypothesis is not entirely supported by physiological facts and does not take into consideration mitochondrial dysfunction that has been repeatedly reported in both human and animal TBI. Although the nature and origin of the events leading to mitochondrial damage may be different, most share a permeabilization of mitochondrial membrane, which therefore may represent a logical target for new therapeutic strategies. Therefore, the proteins mediating these events may represent promising targets for new TBI therapies. Furthermore, mimicking anti-apoptotic proteins, such as Bcl-2 or XIAP, or inhibiting mitochondrial pro-apoptotic proteins, such as Smac/DIABLO, Omi/HTRA2, and ARTS (septin 4 isoform 2) may represent useful novel therapeutic strategies. This review focuses on mechanisms of the mitochondrial membrane permeabilization and its consequences and discusses the current and possible future therapeutic implications of this key event of neuronal death.

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Persistent metabolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts chronic frontal lobe brain atrophy after traumatic brain injury*

Abstract: Persistent metabolic crisis, as reflected by an elevated lactate/pyruvate ratio, in normal appearing posttraumatic frontal lobe, is predictive of the degree of tissue atrophy at 6 months.

Cited by 143 publications

References 24 publications

Early Nonischemic Oxidative Metabolic Dysfunction Leads to Chronic Brain Atrophy in Traumatic Brain Injury

Early Nonischemic Oxidative Metabolic Dysfunction Leads to Chronic Brain Atrophy in Traumatic Brain Injury

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

Mitochondrial Damage: A Target for New Therapeutic Horizons

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