Trafficking of Glucose, Lactate, and Amyloid-β from the Inferior Colliculus through Perivascular Routes

Ball, Kelly K.; Cruz, Nancy F.; Mrak, Robert E.; Dienel, Gerald A.

doi:10.1038/jcbfm.2009.206

Cited by 78 publications

(99 citation statements)

References 41 publications

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“…107,108 Amyloid-beta, 14 C-metabolites of [ 14 C]glucose, and fluorescent tracers are cleared via this pathway by mechanisms involving astrocytic water movements mediated by aquaporins. [109][110][111][112] In our studies, lactate release to blood (22% of glucose influx) accounted for about half the magnitude of underestimation of CMR glc when assayed with [6-14 C]glucose, and follow-up studies indicate that a similar quantity is probably lost via perivascular flow. 23 Clearance of some glucose and lactate from brain via lymphatic drainage after their uptake into brain but before they are metabolized may contribute to the 'missing' quantities of glucose and lactate taken up during exhaustive exercise and not accounted for by oxygen consumption or accumulation in brain.…”

Section: Some Speculations: Hypoglycemic Glycogenolysis Mitochondriasupporting

confidence: 45%

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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Section: Some Speculations: Hypoglycemic Glycogenolysis Mitochondriasupporting

confidence: 45%

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

Dienel

2014

J Cereb Blood Flow Metab

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“…Ab contained within interstitial fluid enters capillary basement membranes, drains into the basement membranes of cerebral arterioles and arteries, reaching leptomeningeal arteries, and out of the base of the skull to cervical lymph nodes Ball et al, 2010). Increasing age leads to arteriosclerosis, diminishing the driving force for perivascular clearance, and resulting in the development of CAA (Schley et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Based on experimental and pathological observations, perivascular drainage of Ab from the brain seems to occur initially along the basement membranes of capillaries and arterioles, then along the walls of cortical and leptomeningeal arteries and out of the base of the skull to cervical lymph nodes (Goldmann et al, 2006;Carare et al, 2008;Ball et al, 2010). Theoretical modeling suggests that perivascular drainage may be driven by the contrary wave that follows arterial pulsations (Schley et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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SummaryDevelopment of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-b (Ab) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Ab contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Ab into the hippocampus or thalamus showed an agerelated reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Ab in the brain in AD and may facilitate development of improved therapeutic strategies to remove Ab from the brain in AD.

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“…2,50 The view presented here proposes that abnormal flow responses partly reflect compensatory changes to optimize oxygen extraction in tissue affected by severe capillary dysfunction. Molecules the size of hemoglobin undergo rapid perivascular clearance, 51,52 during which they must pass through the narrow capillary basement membrane where pericytes are located. Here, CTH would be expected to change as pericytes react to potassium, NO, and a range of vasodilators in much the same way as vascular smooth muscle cells.…”

Section: May 2015mentioning

confidence: 99%

Neurovascular Coupling During Cortical Spreading Depolarization and –Depression

Østergaard

Dreier

Hadjikhani

et al. 2015

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A B Figure 1. A, The importance of capillary flow patterns (yellow arrows) for the efficacy of oxygen extraction. Intravascular colors indicate blood saturation (red, fully oxygenated; darker blue, more deoxygenated) and surrounding darker blue colors indicate lower tissue oxygen tension-adapted from Østergaard et al. 23 Copyright ©2013, The Authors (see: http://creativecommons.org/licenses/by-nc-sa/3.0/). In the resting, normal brain (top), erythrocyte velocities vary greatly among capillaries, with little oxygen being extracted from fast-flowing blood. 22 As cerebral blood flow (CBF) increases (right), capillary flow patterns homogenize in parallel. 22 This phenomenon reduces the functional shunting that otherwise occurs when erythrocytes pass through capillaries at short transit times. Although the mean transit time (MTT) of blood through the capillary bed is related to CBF through the central volume theorem (MTT=CBV/CBF, where CBV is the capillary blood volume), capillary transit time heterogeneity (CTH) indicates the distribution of capillary transit times relative to this mean (eg, in terms of their standard deviation). Both MTT and CTH are measured in seconds, and the degree of functional shunting generally increases as CTH approaches MTT.24 Bottom, Capillary dysfunction, characterized by elevated CTH relative to MTT, and failure of capillary flow patterns to homogenize during hyperemia. The conditions may be the result of pericyte dysfunction, changes in blood viscosity or capillary wall morphology, or external capillary compression. These changes hinder the redistribution of blood across the capillary bed, with less affected capillary paths tending to act as functional shunts for oxygenated blood. Biophysically, the only means of attenuating the accompanying oxygen loss is to reduce transit times across all capillaries, that is, to attenuate CBF and CBF responses. 25 The accompanying reduction in net oxygen supply reduces tissue oxygen tension as cells continue to use oxygen, increasing blood-tissue concentration gradients and net oxygen extraction. 25 With flow responses attenuated, oxygen extraction can be increased from the 30% of normal brain up to near unity, and normal brain function maintained although capillary dysfunction becomes more severe. 25 It is important to note that current state-of-the-art algorithms to generate maps of transit time-related metrics based on perfusion-weighted magnetic resonance imaging or computed tomography cannot distinguish changes in tracer retention caused by prolonged MTT (reduced CBF) from changes caused by capillary flow disturbances (capillary dysfunction). 25 The effects of CTH must therefore be separately modeled to ascertain whether clinical signs of ischemia are indeed caused by limited blood supply or by capillary dysfunction.26 B, The acute changes in capillary morphology that accompany conditions in which CSD are common. In traumatic brain injury (TBI; i), massive swelling of the perivascular astrocytic end feet (AE) and flattening or compression of the...

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Trafficking of Glucose, Lactate, and Amyloid-β from the Inferior Colliculus through Perivascular Routes

Cited by 78 publications

References 41 publications

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

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

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Neurovascular Coupling During Cortical Spreading Depolarization and –Depression

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