bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of [99mTc]HMPAO SPECT with [18F]Fluoromethane PET in Cerebrovascular Disease
Authors: Heiss W.-D. , Herholz K. , Podreka I. , Neubauer I. , Pietrzyk U.
Published: April 2011

Positron emission tomography (PET) of [18F]fluoromethane (FM) and single-photon emission tomography (SPECT) of [99mTc]hexamethylpropyleneamine oxime (HMPAO) were performed under identical conditions within 2 h in 22 patients suffering from cerebrovascular disease (8 ischemic infarction, 2 intracerebral hemorrhages, 7 transient ischemic attacks, and 5 multi-infarct syndrome). While gross pathological changes could be seen in the images of either procedure, focal abnormalities corresponding to transient ischemic deficits or to lesions in multi-infarct syndrome and areas of functional deactivation were sometimes missed on SPECT images. Overall, HMPAO SPECT images showed less contrast between high and low activity regions than the FM PET images, and differences between lesions and contralateral regions were less pronounced (6.4 vs 13.3% difference). Regional cerebral blood flow (rCBF) was calculated from FM PET studies in 14 large territorial regions and the pathological lesion, and the regional values relative to mean flow were compared to the relative HMPAO uptake in an identical set of regions defined on the SPECT images. Among individual patients, the Spearman rank-correlation coefficient between relative rCBF and HMPAO uptake varied between 0.48 and 0.89, with a mean of 0.70. While an underestimation of high flow with SPECT—which was demonstrated in a curvilinear relationship between all relative regional PET and SPECT values—could be corrected by linearization taking into account HMPAO efflux from the brain before metabolic trapping, correspondence of SPECT data with PET rCBF values was not improved since this procedure also increased the variance in high flow areas. In the cerebellum, however, a high HMPAO uptake in SPECT always overestimated CBF in relation to forebrain values; this finding might be due to high capillary density in the cerebellum. The differences observed between SPECT and PET data may be explained by technical and physical properties of the methods and by the incomplete first-pass extraction of HMPAO. Additionally, HMPAO or its metabolites may leak through a damaged blood–brain barrier (as observed in one infarct and in the surrounding of hemorrhages), impairing the contrast between lesion and normal tissue. The presented data indicate that the quantification of rCBF by HMPAO SPECT is limited.
Blood—Brain Transfer and Metabolism of 6-[18F]Fluoro-L-DOPA in Rat
Authors: Reith Jakob , Dyve Suzan , Kuwabara Hiroto , Guttman Mark , Diksic Mirko , Gjedde Albert
Published: April 2011

In a study designed to reveal the rates of blood–brain transfer and decarboxylation of fluoro-L-3,4-dihydroxyphenylalanine (FDOPA), we discovered a major discrepancy between the DOPA decarboxylase activity reported in the literature and the rate of FDOPA decarboxylation measured in the study. “Donor” rats received intravenous injections of 6 mCi fluorine-18-labeled FDOPA. The donor rats synthesized methyl-FDOPA. Arterial plasma, containing both FDOPA and methyl-FDOPA, was sampled from the donor rats at different times and reinjected into “recipient” rats in which it circulated for 20 s. The blood–brain clearance of the mixture of labeled tracers in the plasma was determined by an integral method. The individual permeabilities were determined by linear regression analysis, according to which the average methyl-FDOPA permeability in the blood–brain barrier was twice that of FDOPA, which averaged 0.037 ml g−1 min−1. The permeability ratio was used to determine the fractional clearance from the brain of FDOPA (and hence of methyl-FDOPA), which averaged 0.081 min−1. In the striatum, the measured average FDOPA decarboxylation rate constant ( kD3) was 0.010 min−1, or no more than 1% of the rate of striatal decarboxylation of DOPA measured in vitro and in vivo. We interpreted this finding as further evidence in favor of the hypothesis that striatum has two dopamine (DA) pools, of which only DA in the large pool is protected from metabolism. Hence, no more than 1% of the quantity of fluoro-DA theoretically synthesized was actually retained in striatum.
Use of [11C]Aminocyclohexanecarboxylate for the Measurement of Amino Acid Uptake and Distribution Volume in Human Brain
Authors: Koeppe Robert A. , Mangner Thomas , Betz A. Lorris , Shulkin Barry L. , Allen Richard , Kollros Peter , Kuhl David E. , Agranoff Bernard W.
Published: April 2011

A quantitative positron emission tomographic (PET) method to measure amino acid blood–brain barrier (BBB) transport rate and tissue distribution volume (DV) has been developed using 11C-labeled aminocyclohexanecarboxylate (ACHC), a nonmetabolized amino acid analogue. Dynamic PET data were acquired as a series of 15 scans covering a total of 60 min and analyzed by means of a two-compartment, two-parameter model. Functional images were calculated for the amino acid transport rate constants across the BBB and the amino acid DV in the brain. Results show [11C]ACHC to have an influx rate constant in gray matter of ∼0.03–0.04 ml g−1 min−1, indicating a single-pass extraction fraction of ∼5–7%. The intersubject coefficient of variation was ∼15% while intrasubject variability of repeat scans was only slightly greater than 5%. Studies were performed in 15 young normal volunteer control subjects, 5 elderly controls, 7 patients with probable Alzheimer's disease, and one patient with phenylketonuria. Results indicate that [11C]-ACHC will serve as the basis of a method for measuring amino acid transport rate and DV in the normal and pathological human brain.
Regional Blood—Brain Glucose Transfer and Glucose Utilization in Chronically Hyperglycemic, Diabetic Rats following Acute Glycemic Normalization
Authors: Pelligrino D. A. , Lipa M. D. , Albrecht R. F.
Published: April 2011

Regional rates of brain glucose utilization (rCMRglc) and glucose influx (rJin), along with regional brain tissue glucose concentrations, were measured in chronically hyperglycemic diabetic (CHD) rats following acute glycemic normalization. These results were compared to those obtained in nondiabetic normoglycemic controls. The diabetic rats were evaluated at 6–8 weeks following i.p. streptozotocin injection. All rats were N2O (70%) sedated, paralyzed, and artificially ventilated for study. Acutely normoglycemic (plasma glucose = 7.9 µmol/ml) CHD rats, compared to control (plasma glucose = 8.5 µmol/ml), demonstrated significantly higher ( p < 0.05) rCMRglc and rJin values in 8 of the 11 regions analyzed. Tissue/plasma glucose concentration ratios were significantly greater than control in 9 of 11 regions. Prior to acute glycemic normalization, rCMRglc values in CHD rats were either unchanged or moderately lower than control. These findings indicate that no blood–brain barrier glucose transport repression is present in CHD rats. In fact, the results suggest an increased transport capacity. The increased rCMRglc observed in the acutely normalized CHD rats may be a manifestation of the “hypoglycemic symptoms” observed in chronically hyperglycemic patients following acute glycemic reductions to the normal range. The present results imply that these symptoms are not related to the presence of a relative cerebral glucopenia, as others have suggested.
Amine-Induced Responses of Pial and Penetrating Cerebral Arteries: Evidence for Heterogeneous Responses
Authors: Sercombe R. , Hardebo J. E. , Kåhrström J. , Seylaz J.
Published: April 2011

Middle cerebral arteries (MCAs) of rabbits were compared with two types of small branches (<100-µm outer diameter), penetrating arteries (PAs) and surface arteries (SAs), by determining their mechanical reactivity to several amines and standard contractile agents. Two techniques were employed: (a) measurement of isometric tension of 1-mm rings (MCA, PA, or SA); (b) measurement of perfusion pressure of segments consisting of essentially MCA or essentially PA. Both techniques revealed similar reactivity of the different types of vessel to acetylcholine, i.e., relaxations to a maximum of 52–78%, and similar strong contractile responses to histamine, although the MCA was more sensitive. Under H1 blockade, histamine dilated the PA (both techniques) and the MCA (perfusion technique), but not the SA. Relatively weak contractile responses to serotonin were observed in the MCA (both techniques) and the PA (perfusion technique), but not the SA (isometric tension only); no dilative responses could be elicited. Responses to noradrenaline varied with the vessel considered: The MCA contracted only, whereas the PA weakly contracted or relaxed at basal tone, and many preparations relaxed after precontraction with uridine triphosphate; the SA did not react. Relaxation of precontracted PA by noradrenaline occurred at relatively low concentrations and was antagonized by propranolol at 3 × 10− 7 or 3 × 10− 6 M. These results reveal very significant differences in the segmental reactivity to amines and suggest that noradrenaline released from sympathetic fibers might have opposing actions in the major pial arteries and the smaller penetrating branches.
The Time Course of Intracranial Pathophysiological Changes following Experimental Subarachnoid Haemorrhage in the Rat
Authors: Jackowski A. , Crockard A. , Burnstock G. , Russell R. Ross , Kristek F.
Published: April 2011

The rat subarachnoid haemorrhage (SAH) model was further studied to establish the precise time course of the globally reduced CBF that follows and to ascertain whether temporally related changes in cerebral perfusion pressure (CPP) and intracranial pressure (ICP) take place. Parallel ultrastructural studies were performed upon cerebral arteries and their adjacent perivascular subarachnoid spaces. SAH was induced by a single intracisternal injection of autologous arterial blood. Serial measurements of regional cortical CBF by hydrogen clearance revealed that experimental SAH resulted in an immediate 50% global reduction in cortical flows that persisted for up to 3 h post SAH. At 24 h, flows were still significantly reduced at 85% of control values (p < 0.05), but by 48 h had regained normal values and were maintained up to 5 days post SAH. ICP rose acutely after haemorrhage to nearly 50 mm Hg with C-type pressure waves being present. ICP then fell slowly, only fully returning to control levels at 72 h. Acute hydrocephalus was observed on autopsy examination of SAH animals but not in controls. Reductions in CPP occurred post SAH, but only in the order of 15%, which could not alone account for the fall in CBF that took place. At 48 and, to a lesser extent, 24 h post SAH, myonecrosis confined largely to smooth muscle cells of the immediately subintimal media was observed. No significant changes in the intima or perivascular nerve plexus were seen. Within 24 h of haemorrhage, a limited degree of phagocytosis of erythrocytes by pial lining cells took place. However, early on the second day post SAH, a dramatic increase in the numbers of subarachnoid macrophages arose from a transformation of cells of the pia-arachnoid. This period was characterised by intense phagocytic activity, erythrocytes, fibrin, and other debris being largely cleared over the next 24 h. At 5 days post SAH the subarachnoid macrophage population declined, cells losing their mobile active features to assume a more typical pia-arachnoid cell appearance once more. Our studies indicate that this increasingly utilised small animal model of SAH develops global cortical flow changes only acutely, and it is likely that early vasospasm, secondary to released blood products rather than pressure changes per se, is responsible for the initial cerebral ischaemia that develops. Interestingly, both cerebral arterial vasculopathy and perivascular macrophage phagocytic activity are most marked at ∼48 h following SAH in the rat, a time at which a phase of delayed cerebral arterial narrowing has previously been documented.
Hippocampal Neurons Become More Vulnerable to Glutamate after Subcritical Hypoxia: An in vitro Study
Authors: Kohmura Eiji , Yamada Kazuo , Hayakawa Toru , Kinoshita Akira , Matsumoto Katsumi , Mogami Heitaro
Published: April 2011

The neurotoxicity of glutamate and hypoxia was investigated in vitro on hippocampal neurons, which were obtained from 18-day-old rat fetuses and were maintained for 3 days in culture. Chemically defined medium without glutamate was used and the plating density was low enough that the effect of exogenously added glutamate could be directly evaluated. In the normal culture condition 1 m M glutamate was necessary to cause significant neuronal loss in the following 24 h. In marked contrast, when glutamate was added after subcritical hypoxic stress, a dose of glutamate as low as 10 μ M could exhibit neurotoxicity. Administration of MK-801, a selective noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, could in part reverse this increased susceptibility to low-dose glutamate after hypoxia, although MK-801 could not protect hippocampal neurons from high-dose glutamate. Therefore, both the NMDA receptor and other subclasses of the glutamate receptor may be involved in this neurotoxicity of glutamate. Different mechanisms of glutamate neurotoxicity with high and low doses are discussed. Our results showed that hippocampal neurons exposed to subcritical hypoxia become more vulnerable to glutamate than those without hypoxia. This increased susceptibility is of great interest to understanding the mechanism of slowly ongoing neuronal loss caused by ischemia or epilepsy.
Effect of Nimodipine on Regional Cerebral Glucose Metabolism in Patients with Acute Ischemic Stroke as Measured by Positron Emission Tomography
Authors: Heiss W. -D. , Holthoff V. , Pawlik G. , Neveling M.
Published: April 2011

In a randomized double-blind placebocontrolled study of 27 patients with acute ischemic stroke, the effect on regional CMRglc (rCMRglc) of the calcium channel blocking agent nimodipine administered in addition to routine treatment was investigated. Following computed tomography-supported diagnosis of focal ischemia in the middle cerebral artery territory, positron emission tomography (PET) of 2-[18F]fluoro-2-deoxy-d-glucose (FDG) was performed, and the patients were entered into the study within 48 h after onset of symptoms, randomly receiving either nimodipine (2 mg/h constant i.v. infusion for 5 days, 120 mg/day orally for another 16 days) or carrier/placebo. FDG PET was repeated after completion of therapy. The clinical course was followed during the treatment period and for 6 months after the stroke, using the Mathew Score for early and the Barthel Index for late assessment. During that observation period, five patients died in the nimodipine group and four in the control group. Subsequently, the code was broken, and the clinical and PET data were analyzed in relation to treatment assignment, with the nimodipine group comprising 11 and the control group 12 eligible cases. The two groups were similar with respect to age and sex distribution, initial clinical deficit, and infarct size and location. While the infarct rCMRglc showed comparable slight increases over time in both groups, the metabolic changes in the other evaluated regions (contralateral infarct mirror region, ipsi- and contralateral cerebral gray matter, contra- and ipsilateral cerebellar hemispheres) differed significantly between treatment groups (side x region x treatment interaction p < 0.025). In the control group, major improvement was found only in contralateral cerebrum (7.4%), whereas the nimodipine group had bilaterally increased rCMRglc of morphologically intact cerebral (14.6 and 17.1%, respectively) and, to a lesser degree, cerebellar (6.9 and 10.0%, respectively) structures. Likewise, progress of (postacute) rehabilitation was significantly (p1 < 0.05) better in the nimodipine treated patients (median change of Barthel Index = 40 vs. 2.5), although their clinical improvement during the first 3 weeks did not differ from the controls' (median change of Mathew Score = 12 and 11.5, respectively). These results lend further support to the notion that nimodipine treatment is of benefit in acute ischemic stroke. Since action on the infarct proper is unlikely when the drug is given many hours after the ischemic attack, it may be concluded that nimodipine exerts its beneficial effect by ameliorating the functional impairment of morphologically intact tissue surrounding the focal ischemia and by improving the metabolic deactivation of remote brain structures.
Regional Cerebral Glucose Metabolism is Normal in Young Adults with down Syndrome
Authors: Schapiro Mark B. , Grady Cheryl L. , Kumar Anand , Herscovitch Peter , Haxby James V. , Moore Angela M. , White Beverly , Friedland Robert P. , Rapoport Stanley I.
Published: April 2011

Regional CMRglc (rCMRglc) values were measured with [18F]2-fluoro-2-deoxy-d-glucose (18FDG) and positron emission tomography (PET), using a Scanditronix PC-1024-7B scanner, in 14 healthy, noninstitutionalized subjects with trisomy 21 (Down syndrome; DS) (mean age 30.0 years, range 25–38 years) and in 13 sex-matched, healthy volunteers (mean age 29.5 years, range 22–38 years). In the DS group, mean mental age on the Peabody Picture Vocabulary Test was 7.8 years and dementia was not present. Resting rCMRglc was determined with eyes covered and ears occluded in a quiet, darkened room. Global gray CMRglc equaled 8.76 ± 0.76 mg/100 g/min (mean ± SD) in the DS group as compared with 8.74 ± 1.19 mg/100 g/min in the control group (p > 0.05). Gray matter regional measurements also did not differ between groups. The ratio of rCMRglc to global CMRglc, calculated to reduce the variance associated with absolute rCMRglc, and right/left ratios did not show any consistent differences. These results show that healthy young DS adults do not have alterations in regional or global brain glucose metabolism, as measured with 18FDG and PET, prior to an age at which the neuropathological changes in Alzheimer disease are reported to occur.
Brain Damage in a New Hemorrhagic Shock Model in the Rat Using Long-Term Recovery
Authors: Yamauchi Yoichi , Kato Hiroyuki , Kogure Kyuya
Published: April 2011

A new shock model in the rat using hemorrhagic hypotension for production of brain damage is described. Hemorrhagic shock was induced by lowering arterial blood pressure with bleeding. The MABP was maintained at ∼25 mm Hg, accompanied by isoelectric EEG, and then shed blood was retransfused. At 1 week of recovery, morphological and 45Ca autoradiographic changes were examined. No brain damage was observed in rats after 1 min of isoelectric EEG. Mild neuronal damage in the hippocampal CA1 subfield was seen in some animals after 2 min of isoelectric EEG. Severe and consistent neuronal loss in the hippocampal CA1 subfield was recognized after 3 min of isoelectric EEG. Additional damage was also seen in the dentate hilus and the thalamus in some animals. This model can be used to study the pathophysiology of postshock brain damage and to assess new therapies following shock.
Decrease in Perfusion of Cerebral Capillaries during Incomplete Ischemia and Reperfusion
Authors: Ennis Steven R. , Keep Richard F. , Schielke Gerald P. , Betz A. Lorris
Published: April 2011

The effect of unilateral, incomplete cerebral ischemia on CBF, unidirectional flux of α-aminoisobutyric acid (AIB) and sodium, and number of perfused capillaries during ischemia and reperfusion was measured in the cortex of gerbils with symptomatic ischemia. Three hours of unilateral carotid occlusion reduced the CBF to the ipsilateral cortex by 81%, with a smaller 30% decrease in the contralateral cortex. Following 11 min of reperfusion, CBF in the ipsilateral cortex returned to the preischemic value, while the contralateral blood flow decreased to 50% of control. The transfer constants for AIB and sodium in the ipsilateral cortex were reduced by 67 and 53%, respectively, after 3 h of ischemia, with no change in the contralateral cortex. The transfer constant for AIB remained decreased by 48% during the first 20 min of reperfusion, while that for sodium returned to its control value. The number of perfused capillaries was reduced 54% by 3 h of ischemia and remained decreased by 20% after 11 min of reperfusion. These data indicate that 3 h of unilateral carotid occlusion reduces the number of perfused capillaries in the ipsilateral cortex during the ischemic period. Further, the early reperfusion phase is characterized by a mismatch between capillary perfusion and CBF. Finally, early in the postischemic phase, sodium transport undergoes a selective stimulation, probably as a result of stimulation of ion transport.
Carbohydrate and Energy Metabolism during the Evolution of Hypoxic-Ischemic Brain Damage in the Immature Rat
Authors: Palmer Charles , Brucklacher Robert M. , Christensen Melanie A. , Vannucci Robert C.
Published: April 2011

The brain damage that evolves from perinatal cerebral hypoxia-ischemia may involve lingering disturbances in metabolic activity that proceed into the recovery period. To clarify this issue, we determined the carbohydrate and energy status of cerebral tissue using enzymatic, fluorometric techniques in an experimental model of perinatal hypoxic-ischemic brain damage. Seven-day postnatal rats were subjected to unilateral common carotid artery ligation followed by 3 h of hypoxia with 8% oxygen at 37°C. This insult is known to produce tissue injury (selective neuronal necrosis or infarction) predominantly in the cerebral hemisphere ipsilateral to the carotid artery occlusion in 92% of the animals. Rat pups were quick-frozen in liquid nitrogen at 0, 1, 4, 12, 24, or 72 h of recovery; littermate controls underwent neither ligation nor hypoxia. Glucose in both cerebral hemispheres was nearly completely exhausted during hypoxia-ischemia, with concurrent increases in lactate to 10 mmol/kg. During recovery, glucose promptly increased above control values, suggesting an inhibition of glycolytic flux, as documented in the ipsilateral cerebral hemisphere by measurement of glucose utilization (CMRglc) at 24 h. Tissue lactate declined rapidly during recovery but remained slightly elevated in the ipsilateral hemisphere for 12 h. Phosphocreatine (P∼Cr) and ATP in the ipsilateral cerebral hemisphere were 14 and 26% of control (p < 0.001) at the end of hypoxia-ischemia; total adenine nucleotides (ATP + ADP + AMP) also were partially depleted (–46%). During the first hour of recovery, mean P∼Cr was replenished to within 90% of baseline, whereas mean ATP was incompletely restored to 68–81% of control (p < 0.05). Individual ATP and total adenine nucleotide values were >2 SD below control levels in 17/24 (71%) brains at all intervals of recovery. Both ATP and total adenine nucleotides were inversely correlated with tissue water content, reflecting the extent of cerebral edema. No major alterations in the high-energy phosphate reserves occurred in the contralateral cerebral hemisphere either during or following hypoxia-ischemia. Thus, following perinatal cerebral hypoxia-ischemia, ATP and total adenine nucleotides never recover completely in brains undergoing damage but rather are permanently depleted to levels that reflect the severity of tissue injury. Recovery of P∼Cr to near normal levels can occur despite evolving brain damage. The findings have relevance to the assessment of asphyxiated newborn humans using magnetic resonance spectroscopy.
Ornithine Decarboxylase Activity and Putrescine Levels in Reversible Cerebral Ischemia of Mongolian Gerbils: Effect of Barbiturate
Authors: Paschen Wulf , Hallmayer Joachim , Mies Günter , Röhn Gabriele
Published: April 2011

Reversible cerebral ischemia was produced in anesthetized Mongolian gerbils by occluding both common carotid arteries. After 5 min of ischemia, brains were recirculated for 8 or 24 h. Treated animals received a single intraperitoneal injection of pentobarbitol (50 mg/kg) immediately after the anuerysm clips were removed. At the end of the experiments, animals were reanesthetized and their brains frozen in situ. Tissue samples were taken from the cerebral cortex, lateral striatum, CA1 subfield of the hippocampus, thalamus, and cerebellum for measuring ornithine decarboxylase (ODC) activity and putrescine levels. In addition, 20-μm-thick coronal tissue sections were taken from the level of the striatum and stained with hematoxylin/eosin for evaluating the extent of ischemic neuronal necrosis in the lateral striatum. In control animals ODC activity and putrescine levels amounted, respectively, to 0.32 ± 0.03 nmol/g/h and 10.2 ±0.5 nmol/g in the cerebral cortex; 0.34 ± 0.02 nmol/g/h and 12.8 ± 0.5 nmol/g in the lateral striatum; 0.58 ± 0.05 nmol/g/h and 10.5 ± 0.7 nmol/g in the hippocampal CA1 subfield; 0.35 ± 0.01 nmol/g/h and 9.8 ± 0.4 nmol/g in the thalamus; and 0.25 ± 0.01 nmol/g/h and 8.3 ± 0.6 nmol/g in the cerebellum. After 5 min cerebral ischemia and 8 h recirculation, a significant 7- to 16-fold increase in ODC activity was observed in all forebrain structures studied. Following 24 h recirculation, ODC activity normalized in the cortex, striatum, and thalamus but was still significantly above control values in the hippocampal CA1 subfield. In the cerebellum ODC activity did not change significantly. Putrescine levels were significantly increased in all forebrain structures after 8 h (two- to threefold) and even more after 24 h recirculation (up to fivefold). In barbiturate-treated animals, ODC activity was not significantly changed in relation to untreated ones. There was, however, a trend to higher activity in the cerebral cortex, lateral striatum, and hippocampal CA1 subfield. Barbiturate did not produce a significant effect on postischemic putrescine levels except in the CA1 subfield. Here the putrescine content of treated animals was significantly below that found in untreated ones. In the lateral striatum, severe cell damage (>90% of neurons were necrotic) was observed in 5 of 12 untreated animals but in none of the barbiturate-treated ones (<10% of neurons necrotic). In animals with severe cell necrosis in the lateral striatum, putrescine levels amounted to 70.9 ± 3.4 nmol/g but to only 32.0 ± 2.9 nmol/g in animals in which <10% of neurons were affected (p ⩽ 0.001).
Stability of Brain Intracellular Lactate and 3P-Metabolite Levels at Reduced Intracellular pH during Prolonged Hypercapnia in Rats
Authors: Cohen Yoram , Chang Lee-Hong , Litt Lawrence , Kim Francis , Severinghaus John W. , Weinstein Philip R. , Davis Richard L. , Germano Isabelle , James Thomas L.
Published: April 2011

The tolerance of low intracellular pH (pHi) was examined in vivo in rats by imposing severe, prolonged respiratory acidosis. Rats were intubated and ventilated for 10 min with 20% CO2, for 75 min with 50% CO2, and for 10 min with 20% CO2. The maximum Paco2 was 320 mm Hg. Cerebral intracellular lactate, pHi, and high-energy phosphate metabolites were monitored in vivo with 31P and 1H nuclear magnetic resonance (NMR) spectroscopy, using a 4.7-T horizontal instrument. Within 6 min after the administration of 50% CO2, pHi fell by 0.57 ± 0.03 unit, phosphocreatine decreased by ∼20%, and Pi increased by ∼100%. These values were stable throughout the remainder of the hypercapnic period. Cerebral intracellular lactate, visible with 1H NMR spectroscopy in the hyperoxic state, decreased during hypercapnia, suggesting either a favorable change in oxygen availability (decreased lactate production) or an increase in lactate clearance or both. All hypercapnic animals awakened and behaved normally after CO2 was discontinued. Histological examination of cortical and hippocampal areas, prepared using a hematoxylin and eosin stain, showed no areas of necrosis and no glial infiltrates. However, isolated, scattered, dark-staining, shrunken neurons were detected both in control animals (no exposure to hypercapnia) and in animals that had been hypercapnic. This subtle histological change could represent an artifact resulting from imperfect perfusion-fixation, or it could represent subtle neurologic injury during the hypercapnia protocol. In summary, extreme hypercapnia and low pHi (∼6.5) are well tolerated in rats for periods up to 75 min if adequate oxygenation is maintained. The prolonged stability of metabolite concentrations during hypercapnia makes its use convenient for in vivo animal studies of the relevance of pHi to brain injury.
Contractile Responses to Endothelin in Feline Cortical Vessels in situ
Authors: Robinson M. J. , McCulloch J.
Published: April 2011

In this study in chloralose-anaesthetised cats, the vasomotor responses of individual pial vessels on the cortical surface to perivascular subarachnoid microapplication of endothelin were examined. Endothelin (3 × 10−10-3 × 10−6 M) induced marked vasoconstriction of pial arterioles (-33.5 ± 3.8% at 3 × 10−6 M) and pial veins (-35.1 ± 2.7% at 3 × 10−6 M). The concentration of endothelin inducing half-maximal response was in the nanomolar range, with pial veins being slightly more sensitive to the peptide than pial arterioles. Vasoconstrictions induced by endothelin were extremely prolonged, persisting for ∼90 min after a single microapplication. Arterioles constricted by endothelin remained responsive to perivascular microapplication of K+ (10 m M) or alkalotic CSF (pH 7.48).
Reduction of Functional Capillary Density in Human Brain after Stroke
Authors: Gjedde Albert , Kuwabara Hiroto , Hakim Antoine M.
Published: April 2011

The blood flow of brain tissue often returns to normal after an ischemic episode. As “luxury” rather than “reactive” reperfusion, this hyperemia is associated with low metabolism. It is not known to what extent the high blood flow accompanies a high, normal, or low density of capillaries. The resolution of this question may indicate whether the functional capillary density is variable and, if so, whether it is coupled to blood flow or metabolism. To answer these questions, we defined functional capillaries as capillaries that transport glucose. We then calculated the density of functional capillaries ( Dcap) and the mean time of transit of blood through the capillaries ( tcap) from hemodynamic variables obtained in vivo by positron tomography of five patients afflicted by cerebral ischemic stroke. Each patient was studied twice, within 36 h of the insult and 1 week later. We identified nominally “ischemic” regions in the first study as cortical gray matter regions, contiguous with the ischemic focus, in which the magnitude of blood flow did not exceed 20 ml 100 g−1 min−1. In these regions, values of metabolism and functional capillary density were proportionately low compared with normal values obtained in the contralateral hemisphere. The studies revealed a reduction of the functional density of exchange vessels in postischemic brain tissue as soon as 36 h after the insult. In “ischemic” regions, within 36 h of the insult, the net extraction of oxygen was inversely related to the capillary transit time and appeared to be limited mainly by the low functional density of the capillaries. Contrary to expectations, the reduced density persisted, even when more than adequate perfusion of the tissue returned. For these reasons, we concluded that changes of the capillary density were associated with changes of the metabolism of the tissue rather than with blood flow.
The Influence of Mild Body and Brain Hypothermia on Ischemic Brain Damage
Authors: Minamisawa Hiroaki , Nordström Carl-Henrik , Smith Maj-Lis , Siesjö Bo K.
Published: April 2011

The influence of brain and body temperature on ischemic brain damage, notably on the density and distribution of selective neuronal vulnerability, was studied in SPF-Wistar rats subjected to 15 min of forebrain ischemia induced by bilateral occlusion of the common carotid arteries combined with arterial hypotension (50 mm Hg) in a room air environment. In one group of animals, the body temperature was maintained at 37°C but no attempt was made to prevent heat losses from the ischemic brain; i.e., the head was not heated during ischemia. Under those conditions the temperature of the caudoputamen and at a subcutaneous site over the skull bone spontaneously fell to ∼32°C. In four other groups, both the rectal and the subcutaneous skull temperatures were maintained at 38, 37, 35, and 33°C during the ischemia. Our results confirm those recently reported when brain temperature was varied during 20 min of ischemia, with body temperature kept constant. Thus, the histopathological outcome of the brain damage, as assessed after 7 days of recovery, was strongly temperature dependent. Whereas ischemia at 37–38°C consistently caused neuronal necrosis in the hippocampus, neocortex, and caudoputamen, spontaneous cooling of the brain during ischemia at a rectal temperature of 37°C significantly reduced the ischemic damage. Intentional lowering of temperature to 35°C markedly reduced and to 33°C virtually prevented neuronal necrosis in some but not all of the regions studied. While damage to the caudoputamen was extremely temperature sensitive, that affecting the CA1 sector of the hippocampus, and particularly the lateral reticular nucleus of the thalamus, was less so. Our results suggest that whatever biochemical events are responsible for selective neuronal vulnerability, they are temperature sensitive; however, since there are differences in sensitivity between different parts of the brain, more than one mechanism may be involved.
Effect of Adenosine on Total and Regional Cerebral Blood Flow of the Newborn Piglet
Authors: Laudignon Nicole , Beharry Kae , Rex Joan , Aranda Jacob V.
Published: April 2011

The effect of adenosine on total and regional CBF, measured by radiolabeled microspheres, was assessed in 16 anesthetized and ventilated newborn (1–3 days old) piglets. They received a ventriculocisternal perfusion containing either CSF alone (controls, n = 5) or CSF mixed with two different concentrations of adenosine (15 min each) randomly assigned using the following doses: 0.1 μ M, 10 μ M, 100 μ M, 1 m M (n = 4), or 10 m M (n = 6). Mean CSF adenosine concentration (by HPLC) before perfusion was 0.6 ± 0.4 μ M. Total and regional CBF were not altered by the perfusion of CSF alone. All adenosine concentrations, except at low doses, increased total and regional CBF, without altering the cerebral metabolic rate for oxygen. Brainstem blood flow was increased by a mean of 110, 145, 306, and 378% with 10 μ M, 100 μ M, 1 m M, and 10 m M concentrations, respectively. Except for the highest concentration, CBF response was dose dependent in each region of the brain with the following order of potency: brainstem > periventricular area > telencephalon, midbrain, total brain, and cerebellum. These data indicate that, in the newborn, adenosine is a potent vasodilator of cerebral vessels. If the newborn brain can synthesize appropriate concentrations of adenosine, this nucleoside may play a major role in regional CBF regulation during the neonatal period.
Preferential Metabolic Activation of Subcortical Brain Areas by Acute Administration of Nicotine to Rats
Authors: McNamara Dennis , Larson Denise M. , Rapoport Stanley I. , Soncrant Timothy T.
Published: April 2011

Cerebral metabolic and behavioral effects of acutely administered nicotine were measured in rats in relation to dose. Nicotine 0.1, 1, or 10 mg/kg or vehicle was administered intraperitoneally to 3-month-old male Fischer-344 rats that had been pretreated with hexamethonium bromide 5 mg/kg i.p. to reduce peripheral autonomic effects. Regional CMRglc (rCMRglc) values were measured, using the quantitative autoradiographic [14C]-2-deoxy-d-glucose method, in 71 brain regions, beginning 3 min after nicotine or vehicle administration. Intensity of body tremor, scored by a blinded rater, was dose related and peaked at 3 min after nicotine injection. rCMRglc rose in a dose-related manner: Nicotine 0.1 mg/kg had no significant effect in any region, whereas 1 mg/kg elevated rCMRglc significantly in 21 regions (mean rise 20%) and 10 mg/kg produced generalized (56 regions) and greater (mean rise 50%) increases in rCMRglc. Nicotine 1 mg/kg activated thalamic nuclei, cerebellum, geniculate nuclei, superior colliculus, median raphe, reticular formation, and the habenulointerpeduncular pathway, but was without effect in the telencephalon. Effects of nicotine in the hindbrain were related anatomically to reported distributions of [3H]nicotine and [3H]acetylcholine but not [125I]α-bungarotoxin binding sites, implying that the former ligands label functional nicotine receptors. The pattern of change in rCMRglc after nicotine administration suggests that its cognitive effects in humans are due to augmented arousal/attention and visual processing rather than to direct neocortical or hippocampal activation.
Origins and Pathways of Choline Acetyltransferase—Positive Parasympathetic Nerve Fibers to Cerebral Vessels in Rat
Authors: Suzuki Norihiro , Hardebo Jan Erik , Owman Christer
Published: April 2011

The presence of cholinergic nerve fibers in the brain vasculature has been a matter of controversy, partly due to the lack of a reliable histochemical marker. Accordingly, no distinct information about the origin and pathways for such fibers has been available. In the present study on the rat pial vasculature, utilizing a choline acetyltransferase (ChAT) antibody, which is able to demonstrate this enzyme in peripheral nervous tissue, evidence was obtained for an innervation by cholinergic fibers of large pial arteries. Vasoactive intestinal polypeptide (VIP) was present in or in close association with these fibers. By the aid of the retrograde axonal tracer True Blue (TB) applied to the middle cerebral arterial wall, such fibers were shown to originate in a subgroup of ChAT-positive cells in the sphenopalatine, otic, and internal carotid ganglia, which, in addition, contained VIP. The ChAT-positive pial nerve fibers were few in relation to the VIP-immunoreactive fibers, as was also illustrated by the few TB-positive cells in the ganglia that were ChAT positive as compared with the number of cells that were VIP positive. Only a small population of ChAT-containing neurons in these ganglia appeared to project to the pial vessels. The pathway from the sphenopalatine ganglion is via a membranous structure on the medial orbital wall, through the ethmoidal foramen, and along the internal ethmoidal artery to reach the circle of Willis. The fibers from the internal carotid and otic ganglia probably bridge to the internal carotid artery in the carotid canal, those from the otic ganglion after an initial course in the lesser superficial petrosal nerve. In addition, a weak accumulation of ChAT immunoreactivity was observed along thick nerve bundles in the wall of large and smaller pial arteries. VIP fibers were running at some locations along these nerve bundles.
The Difference in Vascular Volume between Cerebrum and Cerebellum is in the Pia Mater
Authors: Holash J. A. , Sugamori K. , Stewart P. A.
Published: April 2011

Previous studies using intravascular tracers have shown that the apparent vascular volume in the cerebellum is 10–60% higher than that in the cerebrum. We questioned whether the extravascular volume in the cerebellum could be accounted for by the vasculature of the pia mater that covers its highly infolded surface. Estimates of vascular volume were made using a previously reported point-counting method. Two counts were done: one in which only intraparenchymal vessels were included, and a second one in which both intraparenchymal vessels and pial vessels were included. We found no differences in intraparenchymal vascular volume between cerebellum and cerebrum. When the pial vessels are included, however, the cerebral vascular volume increases by <6%, whereas the cerebellar vascular volume increases by >30%. We suggest that the higher cerebellar vascular volume measured using intravascular tracers is due to inclusion of the pial vasculature. Since pial vessels do not express blood–brain barrier characteristics as prominently as intraparenchymal vessels, we further suggest that estimates of barrier permeability in cerebellum should not be made using simple models developed for cerebral tissue.
The Relationship between Global and Local Changes in PET Scans
Authors: Friston K. J. , Frith C. D. , Liddle P. F. , Dolan R. J. , Lammertsma A. A. , Frackowiak R. S. J.
Published: April 2011

In order to localize cerebral cognitive or sensorimotor function, activation paradigms are being used in conjunction with PET measures of cerebral activity (e.g., rCBF). The changes in local cerebral activity have two components: a global, region independent change and a local or regional change. As the first step in localizing the regional effects of an activation, global variance must be removed by a normalization procedure. A simple normalization procedure is division of regional values by the whole brain mean. This requires the dependence of local activity on global activity to be one of simple proportionality. This is shown not to be the case. Furthermore, a systematic deviation from a proportional relationship across brain regions is demonstrated. Consequently, any normalization must be approached on a pixel-by-pixel basis by measuring the change in local activity and change in global activity. The changes associated with an activation can be partitioned into global and local effects according to two models: one assumes that the increase in local activity depends on global values and the other assumes independence. It is shown that the increase in activity due to a cognitive activation is independent of global activity. This independence of the (activation) condition effect and the confounding linear effect of global activity on observed local activity meet the requirements for an analysis of covariance, with the “nuisance” variable as global activity and the activation condition as the categorical independent variable. These conclusions are based on analysis of data from 24 scans: six conditions over four normal subjects using a verbal fluency paradigm. A technique is described based on ANCOVA and using statistical parametric mapping to localize foci in the brain that have been significantly perturbed by the cognitive tasks. This technique represents a fundamental and necessary departure from ROI-based approaches allowing the separation of global and local effects pixel by pixel, and provides an image of affected regions whose significance can be quantified. The specificity and sensitivity of the described method of change detection is assessed.
Positron Emission Tomographic Measurements of Cerebral Glucose Utilization Using [1-11C]D-Glucose
Authors: Blomqvist G. , Stone-Elander S. , Halldin C. , Roland P. E. , Widén L. , Lindqvist M. , Swahn C.-G. , Långström B. , Wiesel F. A.
Published: April 2011

Regional CMRglc was measured in seven healthy volunteers with positron emission tomography using [1-11C]D-glucose. Regional CBF was measured using [11C]fluoromethane. The arteriovenous differences of unlabeled glucose and oxygen together with 11C metabolites were also measured. In addition to the loss of [11C]CO2, a loss of acidic 11C metabolites was also detected. A three-compartment model was applied to the tracer data in the time interval 0–24 min. After correction for the loss of 11C metabolites, the tracer method gave an average CMRglc of 26.4 ± 1.9 (SD) μmol/100 g/min, close to the value obtained with the Fick principle. After correction for the loss of [11C]CO2 only, the tracer method gave 23.6 ± 2.1 μmol/100 g/min, compatible with (1/6) CMRO2, obtained with the Fick principle. These results and the time course of the loss of acidic 11C metabolites are consistent with the presence of nonoxidative metabolism of glucose that causes an early loss of mainly [11C]lactate after a bolus injection of the tracer. This implies that [1-11C]D-glucose measures the rate of glucose oxidation rather than the total CMRglc. The experiments using [1-11C]D-glucose were compared to five analogous experiments using [U-11C]D-glucose together with [15O]H2O as a flow tracer. After correction for the loss of [11C]CO2, the two glucose tracers gave similar global values of CMRglc and other parameters associated with glucose utilization, but with labeling in the carbon-1 position, the loss of [11C]CO2 was substantially delayed and the contrast between gray and white matter was improved. A kinetic model for [1-11C]D-glucose for use in PET studies without the simultaneous measurement of rCBF and the loss of 11C metabolites is proposed.
Kinetic Model of 2-Deoxyglucose Metabolism Using Brain Slices
Authors: Newman George C. , Hospod Frank E. , Patlak Clifford S.
Published: April 2011

A six-compartment, nine-parameter kinetic model of 2-deoxyglucose (2DG) metabolism, which includes bidirectional tissue transport, phosphorylation, two-step dephosphorylation, phosphoisomerization, and conjugation to UDP and macromolecules, has been derived. Data for analysis were obtained from 540- and 1,000-μm-thick hippocampal and hypothalamic brain slices, which were incubated in buffer containing [14C]2DG, frozen, extracted with perchlorate, and separated on anion-exchange columns. Solutions of the equations of the model were fit to the data by means of nonlinear least-squares analysis. These studies suggest that dephosphorylation is adequately described by a single reaction so that the model reduces to eight parameters. The in vitro rate constants for transport, phosphorylation, and dephosphorylation are very similar to prior in vivo results. The phosphoisomerization rate constant is similar to dephosphorylation, so glycosylated macromolecules slowly accumulate and gradually assume larger relative importance as other compounds disappear more rapidly. Rate constants for 540-μm slices from hypothalamus and hippocampus are similar, while 1,000-μm slices have smaller tissue transport constants and larger phosphorylation constants. The rate equation for glucose utilization of this model is relatively insensitive to uncertainties regarding the rate constants. Including later metabolic components in kinetic models improves the calculations of glucose utilization with long isotope exposures.
Cortical Microcirculation in a New Model of Focal Laser-Induced Secondary Brain Damage
Authors: Lindsberg Perttu J. , Frerichs Kai U. , Burris Jennifer A. , Hallenbeck John M. , Feuerstein Giora
Published: April 2011

To study the causes of spatial and temporal evolution of progressive neuroinjury in focal brain ischemia, models with consistent lesion topography are required. In such models, continuous monitoring of the microcirculation in a penumbral area undergoing progressive damage could be possible. We used a fixed-pulse (1.0 s, 40 W) Nd-YAG laser (NYL) to produced discrete brain lesions in rats and monitored the cerebral blood flow (CBF) with laser-Doppler flowmetry (LDF) in nonirradiated areas directly adjacent to the maturing lesion. We also examined the time evolution of the lesion topography over a 4 day period. The lesion volume determined by histopathological methods increased from 3.1 ± 0.5 to 4.5 ± 0.5 mm3 ( p < 0.05) during the first 2 h. Simultaneously, LDF indicated severe hypoperfusion (–60 ± 21%, p < 0.01) at a zone (1 mm distance from the laser lesion) where progressive neuronal degeneration and increased tissue water content (80.0 ± 3.3% versus 76.8 ± 2.1% in normal tissue, n = 7, p < 0.05) were also observed. At a 4 mm distance from the lesion, hyperemic CBF responses were observed, but no histopathological signs or edema. Secondary brain damage progressed up to 4 days (lesion volume of 6.0 ± 0.7 mm3). The NYL-induced brain lesion produced a highly reproducible focal injury and progressive neuronal death in a spatial relationship with micro-circulatory failure and edema formation. The model allows prospective study of tissue state at a discrete zone, which is separate from the initial injury, but susceptible to secondary brain damage.