| 1. |
- Abi-Dargham, A, et al.
(author)
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Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility
- 2000
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In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X. ; 20:2, s. 225-243
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Journal article (peer-reviewed)abstract
- To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient ( k3/ k4). Both kinetic and graphic analyses provided BP and k3/ k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/ k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90 ± 0.06 (mean ± SD of 12 regions) and 0.84 ± 0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72 ± 0.17 and 0.58 ± 0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.
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| 2. |
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| 3. |
- Ahnstedt, Hilda, et al.
(author)
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U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.
- 2015
-
In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 35:3, s. 454-460
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Journal article (peer-reviewed)abstract
- Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.217.
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| 4. |
- Alakurtti, Kati, et al.
(author)
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Long-term test-retest reliability of striatal and extrastriatal dopamine D-2/3 receptor binding : study with [C-11]raclopride and high-resolution PET
- 2015
-
In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 35:7, s. 1199-1205
-
Journal article (peer-reviewed)abstract
- We measured the long-term test-retest reliability of [C-11]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [C-11]raclopride assessments, with a 5-week retest interval. D-2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test-retest studies of [C-11]raclopride binding in the striatum. A novel finding is the relatively low variability of [C-11]raclopride binding, providing suggestive evidence that extrastriatal D-2/3 binding can be studied in vivo with [C-11]raclopride PET to be verified in future studies.
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| 5. |
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| 6. |
- Ansar, Saema, et al.
(author)
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ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat.
- 2006
-
In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 26:Nov 2, s. 846-856
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Journal article (peer-reviewed)abstract
- Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.
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| 7. |
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| 8. |
- Ansar, Saema, et al.
(author)
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Protein kinase C inhibition prevents upregulation of vascular ET(B) and 5-HT(1B) receptors and reverses cerebral blood flow reduction after subarachnoid haemorrhage in rats.
- 2007
-
In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 27:1, s. 21-32
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Journal article (peer-reviewed)abstract
- The pathogenesis of cerebral ischaemia after subarachnoid haemorrhage (SAH) still remains elusive. The purpose of the present study was to examine whether specific protein kinas C (PKC) inhibition in rats could alter the transcriptional SAH induced Endothelin (ET) type B and 5-hydroxytryptamine type 1B (5-HT1B) receptor upregulation and prevent the associated cerebral blood flow (CBF) reduction. The PKC inhibitor RO-31-7549 or vehicle was injected intracisternally after the induced SAH in rats (n = 3 to 10 in each groups for each method). The involvement of the PKC isoforms was investigated with Western blot; only PKC delta and PKC alpha subtypes were increased after SAH RO-31-7549 treatment abolished this. At 2 days after the SAH basilar and middle cerebral arteries were harvested and the contractile response to endothelin-1 (ET-1; ETA and ETB receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1B receptor agonist) were investigated with a myograph. The contractile responses to ET-1 and 5-CT were increased (P < 0.05) after SAH compared with sham operated rats. In parallel, the ETB and 5-HT1B receptor mRNA and protein expression were significantly elevated after SAH, as analysed by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. Administration of RO-31-7549 prevented the upregulated contraction elicited by application of ET-1 and 5-CT in cerebral arteries and kept the ETB and 5-HT1B receptor mRNA and protein levels at pre-SAH levels. Regional and global CBF evaluated by an autoradiographic technique were reduced by 60% 64% after SAH (P < 0.05) and prevented by treatment with RO-31-7549. Our study suggests that PKC plays an important role in the pathogenesis of cerebral ischaemia after SAH.
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| 9. |
- Bendel, Olof, et al.
(author)
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Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory
- 2005
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In: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 25:12, s. 1586-1595
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Journal article (peer-reviewed)abstract
- The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2'-deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.
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| 10. |
- Bergstedt, K., et al.
(author)
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Changes in insulin-like growth factor 1 receptor density after transient cerebral ischemia in the rat : Lack of protection against ischemic brain damage following injection of insulin-like growth factor 1
- 1993
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 13:5, s. 895-898
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Journal article (peer-reviewed)abstract
- Binding of 125I-insulin-like growth factor-1 (125I-IGF-1) to rat brain slices was studied after 15 min of two-vessel occlusion ischemia and 1 h to 4 days of recirculation. Ligand binding in the hippocampus increased at 6 h post ischemia in the CA1 and CA3 regions and the dentate gyrus, suggesting that the IGF-1 receptors were up-regulated, while no change was seen in neocortex and striatum. Intracerebroventricular injections of IGF-1 (2 μg) prior to and after transient cerebral ischemia did not reduce neuronal damage. The increased up-regulation on IGF-1 receptors and the absence of neuroprotection by IGF-1 suggest that the intracellular signal transduction chain activated by the IGF-1 receptor may be interrupted.
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| 11. |
- Bhaskar, S., et al.
(author)
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Baseline collateral status and infarct topography in post-ischaemic perilesional hyperperfusion: An arterial spin labelling study
- 2017
-
In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 37:3, s. 1148-1162
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Journal article (peer-reviewed)abstract
- Focal hyperperfusion after acute ischaemic stroke could be of prognostic value depending upon its spatial localisation and temporal dynamics. Factors associated with late stage (12-24h) perilesional hyperperfusion, identified using arterial spin labelling, are poorly defined. A prospective cohort of acute ischaemic stroke patients presenting within 4.5h of symptom onset were assessed with multi-modal computed tomography acutely and magnetic resonance imaging at 24 +/- 8h. Multivariate logistic regression analysis and receiver operating characteristics curves were used. One hundred and nineteen hemispheric acute ischaemic stroke patients (mean age=71 +/- 12 years) with 24h arterial spin labelling imaging were included. Forty-two (35.3%) patients showed perilesional hyperperfusion on arterial spin labelling at 24h. Several factors were independently associated with perilesional hyperperfusion: good collaterals (71% versus 29%, P < 0.0001; OR=5, 95% CI=[1.6, 15.7], P=0.005), major reperfusion (81% versus 48%, P=< 0.0001; OR=7.5, 95% CI=[1.6, 35.1], P=0.01), penumbral salvage (76.2% versus 47%, P=0.002; OR=6.6, 95% CI=[1.8, 24.5], P=0.004), infarction in striatocapsular (OR=9.5, 95% CI=[2.6, 34], P=0.001) and in cortical superior division middle cerebral artery (OR=4.7, 95% CI=[1.4, 15.7], P=0.012) territory. The area under the receiver operating characteristic curve was 0.91. Our results demonstrate good arterial collaterals, major reperfusion, penumbral salvage, and infarct topographies involving cortical superior middle cerebral artery and striatocapsular are associated with perilesional hyperperfusion.
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| 12. |
- Bhaskar, S., et al.
(author)
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Delay of late-venous phase cortical vein filling in acute ischemic stroke patients: Associations with collateral status
- 2017
-
In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 37:2, s. 671-682
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Journal article (peer-reviewed)abstract
- Evaluation of the venous system may be useful in stroke prognostication and patient selection for acute intervention strategies. We report a novel phenomenon, delayed-late venous phase cortical vein filling, observed on dynamic computed tomography angiography obtained using multidetector computed tomography scanner, in acute ischemic stroke patients. The aim of this study was to examine the frequency of delayed-late venous phase cortical vein filling and assess its association to baseline collateral status. Dynamic computed tomography angiography images of acute ischemic stroke patients, being assessed for reperfusion therapy, were prospectively studied. Delayed-late venous phase cortical vein filling was defined by late venous phase opacification of cortical veins despite contrast clearance from contralateral cortical veins on dynamic computed tomography angiography. Time to peak of maximum arterial enhancement was recorded. A total of 117 patients (mean age = 70.6 +/- 13.3 years; males = 48%) with hemispheric ischemic stroke who underwent acute dynamic computed tomography angiography were included in the study. Overall, 56 (48%) demonstrated delayed-late venous phase cortical vein filling. Poor collateralization (OR = 13.50; 95% CI = (4.2, 43); p <= 0.0001) and longer time to peak of maximum arterial enhancement (OR = 3.2; 95% CI = (1.96, 5.3); p <= 0.0001) were positively associated with delayed-late venous phase cortical vein filling. Delayed-late venous phase cortical vein filling was independently associated with poor baseline collateral status (75% vs. 15%, p <= 0.0001; OR = 14.38; 95% CI = (4.33, 47.8); p <= 0.0001). Delayed-late venous phase cortical vein filling is frequently seen in patients with acute ischemic stroke and is associated with poor baseline collateralization.
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| 13. |
- Björnfot, Cecilia, et al.
(author)
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Assessing cerebral arterial pulse wave velocity using 4D flow MRI
- 2021
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In: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 41:10, s. 2769-2777
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Journal article (peer-reviewed)abstract
- Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial “target-organ” measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.
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| 14. |
- Björnfot, Cecilia, et al.
(author)
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Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults : a 4D flow MRI study
- 2024
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In: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016.
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Journal article (peer-reviewed)abstract
- White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.
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| 15. |
- BLOMQVIST, G
(author)
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Effect of hyperglycemia on rCMRglc in rats
- 1995
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In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X. ; 15:2, s. 349-349
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Journal article (other academic/artistic)
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| 16. |
- Blomqvist, P., et al.
(author)
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Delayed postischemic hypoperfusion : Evidence against involvement of the noradrenergic locus ceruleus system
- 1984
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 4:3, s. 425-429
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Journal article (peer-reviewed)abstract
- This study explores the possibility that the delayed hypoperfusion observed after an ischemic insult might be due to vasoconstriction induced by the release of noradrenaline from nerves originating in the locus ceruleus. Bilateral 6-hydroxydopamine lesions of the ascending bundles from the locus ceruleus were carried out in the caudal mesencephalon of rats. Local CBF was measured with an autoradiographic technique 60 min following the start of recirculation after incomplete forebrain ischemia. No significant differences in CBF between nonoperated, sham-operated, and noradrenaline-depleted animals were observed in any structure of the forebrain. It is concluded that the noradrenergic locus ceruleus system does not contribute to the development of delayed postischemic hypoperfusion.
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| 17. |
- Blomqvist, P., et al.
(author)
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Ischemic brain damage in rats following cardiac arrest using a long-term recovery model
- 1985
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 5:3, s. 420-431
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Journal article (peer-reviewed)abstract
- A model is described in which transient complete cerebral ischemia is induced in rats by intracardiac injection of potassium chloride. The animals were intubated and mechanically ventilated with a nitrous oxide/oxygen (70:30) mixture. Cardiac arrest was achieved following a brief period of ventricular fibrillation. After 5-6 min, the circulation was restored by cardiopulmonary resuscitation and partial exchange transfusion. Local CBF (LCBF) during ischemia and cardiac resuscitation was studied by injection of [14C]iodoantipyrine into the right auricle at various periods during cardiac arrest, and was subsequently analyzed by autoradiography. No radioactive tracer could be visualized in any brain structure, demonstrating the absence of CBF during the cardiac standstill. LCBF was also studied at 5 min and 6.5 h after cardiac resuscitation. Five minutes of recirculation showed an increase in blood flow in all brain structures studied, ranging between 130 and 400% of control values. After 6.5 h of recirculation, the CBF was decreased in 13 of 24 brain structures by 20-50%, concomitantly with the depressed rate of glucose utilization found in 15 brain structures. The neocortical, hippocampal, and striatal concentrations of labile phosphates, lactate, pyruvate, phosphocreatine, glucose, and glucogen were measured 5 min after cardiac arrest. Extensive energy failure and elevation of lactate levels were observed and were similar to earlier reported values. One week following recovery from the ischemic insult, the animals were perfusion-fixed with formaldehyde. The brains were embedded in paraffin, subserially sectioned, and stained with cresyl violet/acid fuchsin. Histopathological changes were assessed by light microscopy as the number of acidophilic or pyknotic neurons. Morphological changes were observed in the hilus of the dentate gyrus, the hippocampal CA1 and subicular regions, the dorsal and lateral septum, the olfactory tubercle, the primary olfactory cortex, the entorhinal cortex, the amygdaloid nuclei, and the reticular nucleus of the thalamus. The distribution of the morphological changes suggests a transsynaptic mechanism, causing neuronal necrosis primarily in the limbic brain areas.
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| 18. |
- Boström, Martina, et al.
(author)
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Irradiation to the young mouse brain caused long-term, progressive depletion of neurogenesis but did not disrupt the neurovascular niche
- 2013
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In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 33:6, s. 935-943
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Journal article (peer-reviewed)abstract
- We investigated the effects of ionizing radiation on microvessel structure and complexity in the hippocampus. We also assessed neurogenesis and the neurovascular niche. Postnatal day 14 male C57BL/6 mice received a single dose of 8Gy to the whole brain and were killed 6 hours, 1 week, 7 weeks, or 1 year later. Irradiation decreased the total number of microvessels and branching points from 1 week onwards and decreased the total microvessel area 1 and 7 weeks after irradiation. After an initial increase in vascular parameter densities, concomitant with reduced growth of the hippocampus, the densities normalized with time, presumably adapting to the needs of the surrounding nonvascular tissue. Irradiation decreased the number of neural stem and progenitor cells in the hippocampus. The relative loss increased with time, resulting in almost completely ablated neurogenesis (DCX(+) cells) 1 year after irradiation (77% decreased 1 week, 86% decreased 7 weeks, and 98% decreased 1 year after irradiation compared with controls). After irradiation, the distance between undifferentiated stem cells and microvessels was unaffected, and very few dying endothelial cells were detected. Taken together, these results indicate that the vasculature adjusts to the surrounding neural and glial tissue after irradiation, not vice-versa.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 March 2013; doi:10.1038/jcbfm.2013.34.
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| 19. |
- Cardell, M., et al.
(author)
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Changes in pyruvate dehydrogenase complex activity during and following severe insulin-induced hypoglycemia
- 1991
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 11:1, s. 122-128
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Journal article (peer-reviewed)abstract
- The effect of severe insulin-induced hypoglycemia on the activity of the pyruvate dehydrogenase enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex during burst suppression EEG, after 10, 30, and 60 min of isoelectric EEG, and after 30 and 180 min and 24 h of recovery following 30 min of hypoglycemic coma. Changes in PDHC activity were correlated to levels of labile organic phosphates and glycolytic metabolites. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 7.1 ± 1.3 U/mg of protein, or 35% of the total PDHC activity. The activity was unchanged during burst suppression EEG whereas the active fraction increased to 81-87% during hypoglycemic coma. Thirty minutes after glucose-induced recovery, the PDHC activity had decreased by 33% compared to control levels, and remained significantly depressed after 3 h of recovery. This decrease in activity was not due to a decrease in the total PDHC activity. At 24 h of recovery, PDHC activity had returned to control levels. We conclude that the activation of PDHC during hypoglycemic coma is probably the result of an increased PDH phosphatase activity following depolarization and calcium influx, and allosteric inhibition of PDH kinase due to increased ADP/ATP ratio. The depression of PDHC activity following hypoglycemic coma is probably due to an increased phosphorylation of the enzyme, as a consequence of an imbalance between PDH phosphatase and kinase activities. Since some reduction of the ATP/ADP ratio persisted and since the lactate pyruvate ratio had normalized by 3 h of recovery, the depression of PDHC most likely reflects a decrease in PDH phosphatase activity, probably due to a decrease in intramitochondrial Ca2+.
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| 20. |
- Cardell, M., et al.
(author)
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Pyruvate dehydrogenase activity in the rat cerebral cortex following cerebral ischemia
- 1989
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 9:3, s. 350-357
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Journal article (peer-reviewed)abstract
- The effect of cerebral ischemia on the activity of pyruvate dehydrogenase (PDH) enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex following 15 min of bilateral common carotid occlusion ischemia and following 15 min, 60 min, and 6 h of recirculation after 15 min of ischemia. In frozen cortical tissue from the same animals, the levels of labile phosphate compounds, glucose, glycogen, lactate, and pyruvate were determined. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 9.6 ± 0.5 nmol CO2/(min-mg protein) or 40% of the total PDHC activity. This fraction increased to 89% at the end of 15 min of ischemia. At 15 min of recirculation following 15 min of ischemia, the PDHC activity decreased to 50% of control levels and was depressed for up to 6 h post ischemia. This decrease in activity was not due to a decrease in total PDHC activity. Apart from a reduction in ATP levels, the acute changes in the levels of energy metabolites were essentially normalized at 6 h of recovery. Dichloroacetate (DCA), an inhibitor of PDH kinase, given to rats at 250 mg/kg i.p four times over 2 h, significantly decreased blood glucose levels from 7.4 ± 0.6 to 5.1 ± 0.3 mmol/L and fully activated PDHC. In animals in which the plasma glucose level was maintained at control levels of 8.3 ± 0.5 μmol/g by intravenous infusion of glucose, the active portion of PDHC increased to 95 ± 4%. In contrast, the depressed PDHC activity at 15 min following ischemia was not affected by the DCA treatment. In both DCA + glucose-treated control and recovery groups, the pyruvate levels decreased by 50%. No significant difference in the lactate levels was seen. We conclude that the depressed postischemic PDHC activity is not due to loss of enzyme protein nor to an increased PDH kinase activity, but is probably due to a decreased activity of PDH phosphatase. This could in turn be secondary to a change in the cellular levels of PDH phosphatase regulators, most probably a decreased intramitochondrial concentration of calcium. The postischemic decrease in PDH activity may be related to the postischemic metabolic depression.
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| 21. |
- Clement, Patricia, et al.
(author)
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Variability of physiological brain perfusion in healthy subjects : A systematic review of modifiers. Considerations for multi-center ASL studies
- 2018
-
In: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X .- 1559-7016. ; 38:9, s. 1418-1437
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Research review (peer-reviewed)abstract
- Quantitative measurements of brain perfusion are influenced by perfusion-modifiers. Standardization of measurement conditions and correction for important modifiers is essential to improve accuracy and to facilitate the interpretation of perfusion-derived parameters. An extensive literature search was carried out for factors influencing quantitative measurements of perfusion in the human brain unrelated to medication use. A total of 58 perfusion modifiers were categorized into four groups. Several factors (e.g., caffeine, aging, and blood gases) were found to induce a considerable effect on brain perfusion that was consistent across different studies; for other factors, the modifying effect was found to be debatable, due to contradictory results or lack of evidence. Using the results of this review, we propose a standard operating procedure, based on practices already implemented in several research centers. Also, a theory of ' deep MRI physiotyping' is inferred from the combined knowledge of factors influencing brain perfusion as a strategy to reduce variance by taking both personal information and the presence or absence of perfusion modifiers into account. We hypothesize that this will allow to personalize the concept of normality, as well as to reach more rigorous and earlier diagnoses of brain disorders.
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| 22. |
- Cselenyi, Z, et al.
(author)
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Quantification of blood flow-dependent component in estimates of beta-amyloid load obtained using quasi-steady-state standardized uptake value ratio
- 2015
-
In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 35:9, s. 1485-1493
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Journal article (peer-reviewed)abstract
- Longitudinal positron emission tomography (PET) imaging of beta-amyloid is used in basic research and in drug efficacy trials in Alzheimer's disease (AD). However, the extent of amyloid accumulation after clinical onset is not fully known. Importantly, regional PET data are typically quantified using the standardized uptake value ratio (SUVR), which according to simulations is sensitive to changes in regional cerebral blood flow (rCBF). We aimed to better understand the potentials of longitudinal amyloid imaging by disentangling the influence of blood flow on SUVR using experimental data. [18F]AV-45 PET data from 101 subjects, ranging from cognitively normal to AD patients, in the Alzheimer's Disease Neuroimaging Initiative were extracted. The relationship between global cortical distribution volume ratio, indicator of rCBF (R1), and SUVR was examined using multilinear regression. There was a significant effect of rCBF on SUVR. The effect increased by disease severity. Results suggest that changes in rCBF can produce apparent changes in SUVR in AD. Therefore, future longitudinal studies should measure amyloid changes in a way not sensitive to this effect, ideally using quantitative PET imaging. Furthermore, the results suggest no true accumulation beyond clinical onset and highlight the risks of longitudinal amyloid imaging in drug trials in AD.
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| 24. |
- Darsalia, Vladimer, et al.
(author)
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Cell number and timing of transplantation determine survival of human neural stem cell grafts in stroke-damaged rat brain.
- 2011
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In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; Jul 1, s. 235-242
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Journal article (peer-reviewed)abstract
- Neural stem cells (NSCs) derived from human fetal striatum and transplanted as neurospheres survive in stroke-damaged striatum, migrate from the implantation site, and differentiate into mature neurons. Here, we investigated how various steps of neurogenesis are affected by intrastriatal transplantation of human NSCs at different time points after stroke and with different numbers of cells in each implant. Rats were subjected to middle cerebral artery occlusion and then received intrastriatal transplants of NSCs. Transplantation shortly after stroke (48 hours) resulted in better cell survival than did transplantation 6 weeks after stroke, but the delayed transplantation did not influence the magnitude of migration, neuronal differentiation, and cell proliferation in the grafts. Transplanting greater numbers of grafted NSCs did not result in a greater number of surviving cells or increased neuronal differentiation. A substantial number of activated microglia was observed at 48 hours after the insult in the injured striatum, but reached maximum levels 1 to 6 weeks after stroke. Our findings show that the best survival of grafted human NSCs in stroke-damaged brain requires optimum numbers of cells to be transplanted in the early poststroke phase, before the inflammatory response is established. These findings, therefore, have direct clinical implications.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 June 2010; doi:10.1038/jcbfm.2010.81.
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| 25. |
- Darsalia, V, et al.
(author)
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Glucagon-like receptor 1 agonists and DPP-4 inhibitors: potential therapies for the treatment of stroke
- 2015
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In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 35:5, s. 718-723
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Journal article (peer-reviewed)abstract
- During the past decades, candidate drugs that have shown neuroprotective efficacy in the preclinical setting have failed in clinical stroke trials. As a result, no treatment for stroke based on neuroprotection is available today. The activation of the glucagon-like peptide 1 receptor (GLP-1) for reducing stroke damage is a relatively novel concept that has shown neuroprotective effects in animal models. In addition, clinical studies are currently ongoing. Herein, we review this emerging research field and discuss the next milestones to be achieved to develop a novel antistroke therapy.
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