Albert Gjedde

Neurologic Sequelae of Domoic Acid Intoxication Due to the Ingestion of Contaminated Mussels

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.

High- and low-affinity transport of D-glucose from blood to brain

Abstract: Measurements of the unidirectional blood‐brain glucose flux in rat were incompatible with a single set of kinetic constants for transendothelial transport. At least two transfer mechanisms were present: a high‐affinity, low‐capacity system, and a low‐affinity, high‐capacity system. The low‐affinity system did not represent passive diffusion because it distinguished between D‐and L‐glucose. The Tmax and Km, for the high‐affinity system were 0.16 mmol 100 g−1 min−1 and 1 mM; for the low‐affinity system, ∼ 5 mmol 100 g−1 min−1 and ∼ 1 M. With these values, physiological glucose concentrations were not sufficient to saturate the low‐affinity system. In normoglycemia, therefore, three independent pathways of glucose transport from blood to brain appear to exist: a high‐affinity facilitated diffusion pathway of apparent permeability 235·10−7 cm s−1, a specific but nonsaturable diffusion pathway of permeability 85·10−7 cm s−l, and a nonspecifc passive diffusion pathway of permeability 2·10−7 cm s−1.

Neuronal-glial glucose oxidation and glutamatergic-GABAergic function

Prior 13C magnetic resonance spectroscopy (MRS) experiments, which simultaneously measured in vivo rates of total glutamate-glutamine cycling (Vcyc(tot)) and neuronal glucose oxidation (CMRglc(ox), N), revealed a linear relationship between these fluxes above isoelectricity, with a slope of ~1. In vitro glial culture studies examining glutamate uptake indicated that glutamate, which is cotransported with Na+, stimulated glial uptake of glucose and release of lactate. These in vivo and in vitro results were consolidated into a model: recycling of one molecule of neurotransmitter between glia and neurons was associated with oxidation of one glucose molecule in neurons; however, the glucose was taken up only by glia and all the lactate (pyruvate) generated by glial glycolysis was transferred to neurons for oxidation. The model was consistent with the 1:1 relationship between ΔCMRglc(ox), N and ΔVcyc(tot) measured by 13C MRS. However, the model could not specify the energetics of glia and γ-amino butyric acid (GABA) neurons because quantitative values for these pathways were not available. Here, we review recent 13C and 14C tracer studies that enable us to include these fluxes in a more comprehensive model. The revised model shows that glia produce at least 8% of total oxidative ATP and GABAergic neurons generate ~18% of total oxidative ATP in neurons. Neurons produce at least 88% of total oxidative ATP, and take up ~26% of the total glucose oxidized. Glial lactate (pyruvate) still makes the major contribution to neuronal oxidation, but ~30% less than predicted by the prior model. The relationship observed between ΔCMRglc(ox), N and ΔVcyc(tot) is determined by glial glycolytic ATP as before. Quantitative aspects of the model, which can be tested by experimentation, are discussed.

Increased Occupancy of Dopamine Receptors in Human Striatum during Cue-Elicited Cocaine Craving

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [11C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Cerebral Blood Flow Measurements by Magnetic Resonance Imaging Bolus Tracking: Comparison with [15O]H2O Positron Emission Tomography in Humans:

In six young, healthy volunteers, a novel method to determine cerebral blood flow (CBF) using magnetic resonance (MR) bolus tracking was compared with [15O]H2O positron emission tomography (PET). The method yielded parametric CBF images with tissue contrast in good agreement with parametric PET CBF images. Introducing a common conversion factor, MR CBF values could be converted into absolute flow rates, allowing comparison of CBF values among normal subjects.

Absolute Cerebral Blood Flow and Blood Volume Measured by Magnetic Resonance Imaging Bolus Tracking: Comparison with Positron Emission Tomography Values:

The authors determined cerebral blood flow (CBF) with magnetic resonance imaging (MRI) of contrast agent bolus passage and compared the results with those obtained by O-15 labeled water (H215O) and positron emission tomography (PET). Six pigs were examined by MRI and PET under normo- and hypercapnic conditions. After dose normalization and introduction of an empirical constant ΦGd, absolute regional CBF was calculated from MRI. The spatial resolution and the signal-to-noise ratio of CBF measurements by MRI were better than by the H215O-PET protocol. Magnetic resonance imaging cerebral blood volume (CBV) estimates obtained using this normalization constant correlated well with values obtained by O-15 labeled carbonmonooxide (C15O) PET. However, PET CBV values were approximately 2.5 times larger than absolute MRI CBV values, supporting the hypothesized sensitivity of MRI to small vessels.

Positron emission tomography of cortical centers of tinnitus

Tinnitus is associated with a wide variety of disorders in the auditory system. Whether generated peripherally or centrally, tinnitus is believed to be associated with activity in specific cortical regions. The present study tested the hypothesis that these cortical centers subserve the generation, perception and processing of the tinnitus stimulus and that these processes are suppressed by lidocaine and masking. Positron emission tomography was used to map the tinnitus-specific central activity. By subtracting positron emission tomography images of regional cerebral blood flow distribution obtained during suppression of the tinnitus from positron emission tomography images obtained during the habitual tinnitus sensation, we were able to identify brain areas concerned with the cerebral representation of tinnitus. Increased neuronal activity caused by tinnitus occurred predominantly in the right hemisphere with significant foci in the middle frontal and middle temporal gyri, in addition to lateral and mesial posterior sites. The results are consistent with the hypothesis that the sensation of tinnitus is associated with activity in cortical regions functionally linked to subserve attention, emotion and memory. For the first time, the functional anatomy of conditions with and without the habitual tinnitus sensation was obtained and compared in the same subjects.

Capillary-oxygenation-level-dependent near-infrared spectrometry in frontal lobe of humans

Brain function requires oxygen and maintenance of brain capillary oxygenation is important. We evaluated how faithfully frontal lobe near-infrared spectroscopy (NIRS) follows haemoglobin saturation (SCap) and how calculated mitochondrial oxygen tension (PMitoO2) influences motor performance. Twelve healthy subjects (20 to 29 years), supine and seated, inhaled O2 air-mixtures (10% to 100%) with and without added 5% carbon dioxide and during hyperventilation. Two measures of frontal lobe oxygenation by NIRS (NIRO-200 and INVOS) were compared with capillary oxygen saturation (SCap) as calculated from the O2 content of brachial arterial and right internal jugular venous blood. At control SCap (78% ± 4%; mean ± s.d.) was halfway between the arterial (98% ± 1%) and jugular venous oxygenation (SVO2; 61% ± 6%). Both NIRS devices monitored SCap (P < 0.001) within ~5% as SvO2 increased from 39% ± 5% to 79% ± 7% with an increase in the transcranial ultrasound Doppler determined middle cerebral artery flow velocity from 29 ± 8 to 65 ± 15 cm/sec. When SCap fell below ~70% with reduced flow and inspired oxygen tension, PMitoO2 decreased (P < 0.001) and brain lactate release increased concomitantly (P < 0.001). Handgrip strength correlated with the measured (NIRS) and calculated capillary oxygenation values as well as with PMitoO2 (r > 0.74; P < 0.05). These results show that NIRS is an adequate cerebral capillaryoxygenation-level-dependent (COLD) measure during manipulation of cerebral blood flow or inspired oxygen tension, or both, and suggest that motor performance correlates with the frontal lobe COLD signal.

Comparative Regional Analysis of 2-Fluorodeoxyglucose and Methylglucose Uptake in Brain of Four Stroke Patients. With Special Reference to the Regional Estimation of the Lumped Constant

The glucose metabolic rate of the human brain can be measured with labeled deoxyglucose, using positron emission tomography, provided certain conditions are fulfilled. The original method assumed irreversible trapping of deoxyglucose metabolites in brain during the experimental period, and it further requires that a conversion factor between deoxyglucose and glucose, the “lumped constant,” be known for the brain regions of interest. We examined the assumption of irreversible trapping of fluorodeoxyglucose metabolites in brain of four patients in 365 normal and 4 recently infarcted regions. The average net, steady-state rate of fluorodeoxyglucose (KD) accumulation in normal regions of the four patients was 0.025 ml g−1 min−1. We also examined the variability of the lumped constant. We first confirmed that methylglucose is not phosphorylated in the human brain. We then estimated the lumped constant from the regional distribution of labeled methylglucose in brain. The average (virtual) volume of distribution of labeled methylglucose in the normal regions was 0.46 ml g−1 and was the same in both gray and white matter structures. The average brain glucose content corresponding to this value was 1.3 μmol g−1, assuming a Michaelis constant (Kt) of 3.7 mM for glucose transport across the blood–brain barrier. The lumped constant varied insignificantly between 0.4 and 0.5 in most regions, with an overall average of 0.44. It did not vary significantly between the patients and was the same in gray and white matter structures, but was inversely related to the calculated metabolic rate. This observation indicates that metabolic rates calculated with a fixed lumped constant (e.g., 0.40) would be slightly underestimated at high metabolic rates and slightly overestimated at low metabolic rates. The average glucose metabolic rates of the 365 normal regions, in which gray matter regions prevailed by 20:1, was 32 μmol 100 g−1 min−1. The average glucose phosphorylation rate in white matter was 20 μmol 100 g−1 min−1 with a lumped constant of 0.45. In the recently infarcted areas, the lumped constants varied from 0.37 to 2.83, corresponding to glucose metabolic rates varying from 2 to 18 μmol 100 g−1 min−1. Two infarct types were identified. In one type, the phosphorylation-limited type, glucose content and the lumped constant were close to normal (1 μmol g−1 and 0.40, respectively). In the other, the transport/flow-limited type, the glucose content was low (0.2 μmol g−1), and the lumped constant in excess of unity. The evidence from the present study upholds the model of Sokoloff et al. in every detail.

Oxygen Consumption of the Living Human Brain Measured after a Single Inhalation of Positron Emitting Oxygen

We measured the rate of washout of 15O-labeled water generated from labeled oxygen accumulated in brain after bolus [15O]O2 inhalation, and compared the washout with that of labeled water measured with H215O. Contrary to the original expectation, the radioactive water generated from labeled oxygen failed to leave the brain tissue at the rate predicted by exogenous water. Therefore, the use of a separately measured value for exogenous water clearance led to an error in the calculation of oxygen consumption. A new method presented in this paper eliminated the error by yielding oxygen consumption in a single oxygen study. We used time-weighted integration to estimate three parameters, including the unidirectional clearance from blood to brain (k1O2), the fractional clearance of the distribution volume in brain (k1O2), and the vascular volume correction (Vo). We showed that the clearance of oxygen from blood to brain can be estimated with acceptable precision by this new approach, and that the new method yields a reliable measure of oxygen consumption.