The Cerebral Metabolism of Glucose and Oxygen Measured With Positron Tomography in Patients With Mitochondrial Diseases

102

Summary:We studied brain energy metabolism by phos phorus magnetic resonance spectroscopy e1p MRS) in 28 patients with mitochondrial cytopathies, and 20 normal control subjects. Fourteen patients had myopathy alone, six had only mild brain symptoms, and eight showed dif ferent degrees of brain involvement. Brain 31p MRS showed a low phosphocreatine content in all patients, accompanied by a high inorganic phosphate in 14 of 28 patients. The average value of the Pi concentration in the patient group was significantly (p = 0.009) different from the control group. The cytosolic pH was normal. From these data were derived a high concentration of ADP (calMitochondrial cytopathies are a heterogeneous group of diseases thought to be due to inherited disorders of mitochondrial function (Schneck et aI., 1973; Berenberg et aI., 1977; Di Mauro et aI., 1985), and characterized by a wide variety of clinical phe notypes (Schneck et aI., 1973; Berenberg et aI., 1977; Pavlakis et aI., 1984; Di Mauro et aI., 1985; Hurko and McKann, 1985; Bourd et aI., 1987; Frackowiak et aI., 1988;Wallace et at., 1988; Berk ovic et aI., 1989). Many patients show symptoms and signs involving multiple organs as in Kearns Sayre syndrome (KSS), in myoclonic epilepsy and Received July 30, 1992; final revision received December 9, 1992; accepted December 9, 1992.Address correspondence and reprint requests to Prof. B. Barbiroli at Istituto di Clinic a N eurologica, via U. Foscolo 7, 40123 Bologna, Italy.Abbreviations used: CPEO, chronic progressive external oph thalmoplegia; DRESS, depth-resolved surface-coil spectros copy; FID, free induction decay; KSS, Kearns-Sayre syndrome; LHON, Leber's hereditary optic neuropathy; MELAS, mito chondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy and ragged-red fibers; MRS, magnetic resonance spectroscopy; PCr, phosphocreatine; PP, phosphorylation potential. 469culated from the creatine kinase equilibrium), a high per cent value of V/V max for ATP biosynthesis, and a low phosphorylation potential, all features showing a de rangement of brain energy metabolism, in all patients with mitochondrial cytopathies. 31p MRS proved to be sensitive enough to disclose a deficit of mitochondrial functionality not only in the affected patients, but also in those without clinically evident brain symptoms. Key Words: Brain bioenergetics-Impaired brain energy me tabolism-Mitochondrial cytopathies-Brain MR spec troscopy.

Section: Discussionmentioning

confidence: 66%

Defective Brain Energy Metabolism Shown by in vivo³¹P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Barbiroli

Montagna

Martinelli

et al. 1993

102

“…These mean CMR O2 and CMR glc values corresponded to respective mean OGI values of 5.6 ± 0.8 and 5.4 ± 0.3 for the HRRH and V data sets, which are in good agreement with prior results. [37][38][39][40][41] The slightly better regional stability in the V data (versus the HRRH data) was likely because of better spatial resolution in the V data, which were presumably less affected by partial volume effects arising from white matter, which has a much lower average metabolic rate than gray matter and a variable percentage within the image voxels can cause significant rate variations even with a constant rate of gray-matter metabolism. However in some small brain regions the metabolic values varied by as much as 50% from the gray-matter mean (Figure 4).…”

Section: Regional Oxidative Demand For Glutamatergic Activity In the mentioning

confidence: 99%

Glutamatergic Function in the Resting Awake Human Brain is Supported by Uniformly High Oxidative Energy

Hyder

Fulbright

Shulman

et al. 2013

104

Rodent 13 C magnetic resonance spectroscopy studies show that glutamatergic signaling requires high oxidative energy in the awake resting state and allowed calibration of functional magnetic resonance imaging (fMRI) signal in terms of energy relative to the resting energy. Here, we derived energy used for glutamatergic signaling in the awake resting human. We analyzed human data of electroencephalography (EEG), positron emission tomography (PET) maps of oxygen (CMR O2 ) and glucose (CMR glc ) utilization, and calibrated fMRI from a variety of experimental conditions. CMR glc and EEG in the visual cortex were tightly coupled over several conditions, showing that the oxidative demand for signaling was four times greater than the demand for nonsignaling events in the awake state. Variations of CMR O2 and CMR glc from gray-matter regions and networks were within ±10% of means, suggesting that most areas required similar energy for ubiquitously high resting activity. Human calibrated fMRI results suggest that changes of fMRI signal in cognitive studies contribute at most ± 10% CMR O2 changes from rest. The PET data of sleep, vegetative state, and anesthesia show metabolic reductions from rest, uniformly 420% across, indicating no region is selectively reduced when consciousness is lost. Future clinical investigations will benefit from using quantitative metabolic measures. Keywords: astrocytes; baseline; field potentials; glutamate; multiunit activity; resting state INTRODUCTIONThe human brain consumes 20% of the body's energy at rest despite being only 2% of total body mass. 1 Normally glucose oxidation is the source of energy production supporting brain function 2 in which gray-matter signaling (i.e., events associated with neuronal firing) is dominated by glutamatergic neurons. 3 Estimates of the fraction of resting brain energy devoted to signaling were originally quite low. 4 But recent experimental studies in rodents and theoretical modeling have converged on the conclusion that majority of the resting energy consumption supports glutamatergic signaling and the energy demand changes linearly with pyramidal neuron firing rates and glutamate neurotransmitter release and reuptake. [5][6][7][8][9] Therefore in rodent models it is possible, to a first order, to show that the resting energy is primarily dedicated to total glutamatergic signaling, and the changes in neuronal signaling relative to a well-defined resting activity level can be used to calibrate changes in energy consumption during functional magnetic resonance imaging (fMRI) experiments. 10,11 In the awake human brain, however, the fraction of resting energy usage devoted to glutamatergic signaling is less well understood. The magnitude of neuronal signaling in the human brain, and by inference the commensurate energy demand, underscores the functional relevance of resting activity and has profound implications for interpreting fMRI experiments in humans. [12][13][14] Given the rapidly increasing use of resting-state fMRI in mapping networks-defined as a...

“…1,2 The oxygen-glucose index of the brain is close to six in the resting state, 3,4 thus the brain consumes, on average, six molecules of oxygen per molecule glucose. The high-energy demand generates the need for a large amount of oxygen delivered via the blood stream.…”

Section: Relevant Basic Numbers Of Oxygen and Glucose Delivery To Thementioning

confidence: 99%

“…of arterial blood 9,000 nmoL/mL Glucose conc. of arterial blood 5,000-6,000 nmoL/mL 53 Oxygen extraction fraction 30%-55% 3,5,6,27,75,93 Glucose extraction fraction 8%-15% ATP concentration of brain tissue 1,000-3,000 nmoL/mL 124,137,138 Total ADP concentration of brain tissue 300 nmoL/mL 124,138 Free ADP concentration of brain tissue 30-35 nmoL/mL [121][122][123] PCr concentration of brain tissue 4,000-5,000 nmoL/mL 123,124,138 Diffusion constant for O2 in brain 78 Assuming mitochondrial oxygen tension close to zero (meaning so low that any further reduction would limit oxidative metabolism), the driving force for oxygen delivery, the gradient between the capillary and mitochondria, can only be increased by an increase in capillary oxygen tension, which in turn requires a decrease of the oxygen extraction fraction. Later, the observation of constant CMRO 2 during pharmacological reductions of CBF led to a modification of the model by incorporating potential changes of cytochrome c oxidase affinity to oxygen during increases in neuronal activity.…”

Section: Differences Of Oxygen and Glucose Supplymentioning

confidence: 99%

The Oxygen Paradox of Neurovascular Coupling

Leithner

Royl

2013

113

100

The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO 2 ). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO 2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO 2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO 2 . This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. Keywords: brain; CMRO 2 ; functional hyperemia; neurovascular coupling; oxygen A quick glance at basic numbers of oxygen and glucose delivery to the brain and cerebral energy metabolism suggests that the most delicate function of cerebral blood flow (CBF) is the delivery of sufficient amounts of oxygen to the tissue where the oxygen reserve is so low that ATP production declines almost immediately once blood flow ceases. Therefore, the intuitive explanation for the rapid and large CBF response to neuronal activation is the supply of the additional oxygen needed. Experimental observations of large CBF responses accompanying small increases of cerebral metabolic rate of oxygen (CMRO 2 ), however, have cast doubt on this intuitive assumption. A number of alternative hypotheses may reconcile the seemingly conflicting findings: (1) A small increase of CMRO 2 may only be possible with a large increase in CBF due to physical limitations of oxygen delivery. Journal of Cerebral Blood(2) The large CBF response may be necessary to ensure oxygen delivery to the areas most distant from blood supply. (3) The large CBF response may not be necessary in its full extent but may have evolved as a safety mechanism ensuring sufficient oxygen supply in situations where oxygen delivery to the brain is impaired. (4) The large CBF response may be necessary for reasons other than oxygen delivery.In this opinion paper, we discuss studies on brain energy metabolism and neurovascular coupling. Based on the available evidence, we hypothesize that the surprisingly large CBF response to neuronal activation has evolved as a safety mechanism for oxygen delivery. To support this hypothesis, we first review basic facts on ...