Gao Shan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 191-194). / Abstracts in English and Chinese. / Abstract in English --- p.i / Abstract in Chinese --- p.iii / Acknowledgement --- p.v / Introduction --- p.vi / Contents --- p.viii / List of tables --- p.xiv / List of figures --- p.xv / Chapter Chapter One --- Literature Review / Chapter 1.1 --- Middle Cerebral Artery (MCA) Stenos --- p.is / Chapter 1.1.1 --- Prevalence of atherosclerotic MCA stenosis --- p.2 / Chapter 1.1.2 --- Methods for diagnosis of MCA stenosis --- p.3 / Chapter 1.1.3 --- Possible mechanism and course of stroke with MCA stenosis --- p.4 / Chapter 1.1.4 --- Treatment and prevention of stroke in patients with MCA stenosis --- p.5 / Chapter 1.2 --- Microembolic Signal (MES) Detection / Chapter 1.2.1 --- Introduction --- p.9 / Chapter 1.2.2 --- Technology --- p.9 / Characteristics of MES / Factors that affect MES detection / Problems of technology / Chapter 1.2.3 --- Clinical application --- p.15 / MES originating from atherosclerotic carotid artery stenosis / MES detection in internal carotid endarterectomy (CEA) / MES detection in patients with MCA stenosis / Predicting value and application in therapeutic trial / References --- p.19 / Chapter Chapter Two --- General Methodology / Chapter 2.1 --- Transcranial Doppler (TCD) Diagnosis for Intracranial Artery Stenosis / Chapter 2.1.1 --- TCD spectrum and common parameters --- p.29 / Chapter 2.1.2 --- Emitting and receiving transducers --- p.29 / Chapter 2.1.3 --- Pulsitility index (PI) --- p.31 / Chapter 2.1.4 --- Insonation depth and flow direction --- p.31 / Chapter 2.1.5 --- Continuous wave (CW) and pulsed wave (PW) --- p.33 / Chapter 2.1.6 --- Normal intracranial arteries through temporal and suboccipital window --- p.33 / Chapter 2.1.7 --- Normal intracranial arteries through orbital window --- p.36 / Chapter 2.1.8 --- Normal extracranial arteries --- p.36 / Chapter 2.1.9 --- TCD diagnosis for intracranial artery stenosis --- p.39 / Chapter 2.1.10 --- Example of multiple intracranial arteries stenosis --- p.39 / Chapter 2.2 --- Microembolic Signal (MES) Detection / Chapter 2.2.1 --- Device of MES monitoring --- p.41 / Chapter 2.2.2 --- Insonated artery and depth --- p.41 / Chapter 2.2.3 --- Axis length of the sample volume --- p.43 / Chapter 2.2.4 --- Fast Fourier Transform (FFT) time window overlap --- p.43 / Chapter 2.2.5 --- Distinguishing embolic signal and artifact with two-gate transducer --- p.45 / Chapter 2.2.6 --- Measurements of embolic signal and threshold --- p.47 / References --- p.45 / Chapter Chapter Three --- Prevalence and Clinical Significance of Microembolic Signal (MES) in Patients with Middle Cerebral Artery (MCA) Stenosis / Chapter 3.1 --- Abstract --- p.50 / Chapter 3.2 --- Introduction --- p.51 / Chapter 3.3 --- Methodology --- p.51 / Patients / Severity of stroke and clinical course / Diagnosis for middle cerebral artery (MCA) stenosis / Microembolic signal (MES) detection / Statistical analysis / Chapter 3.4 --- Results --- p.55 / Baseline information of patients / Prevalence of MES / Relationship between presence of MES and severity of MCA stenosis / Correlation between presence of MES and clinical course in 85 symptomatic patients / Correlation between the count of MES and clinical course in 85 symptomatic patients / Correlation between the presence of MES and further ischemic stroke / Chapter 3.5 --- Discussion --- p.63 / Prevalence of MES / Association between severity of stroke and presence or the number of MES / Predictive value of MES for further stroke / References --- p.66 / Chapter Chapter Four --- Mechanisms of Acute Cerebral Infarction in Patients with Cerebral Artery Stenosis: a Diffusion-weighted Imaging and Microemboli Monitoring study / Chapter 4.1 --- Abstract / Chapter 4.2 --- Introduction --- p.72 / Chapter 4.3 --- Methodology --- p.73 / Patients / Microembolic signal (MES) detection by transcranial Doppler (TCD) / "Magnetic resonance imaging (DWI, MRI and MRA)" / Statistical analysis / Chapter 4.4 --- Results --- p.77 / Severity of MCA stenosis on MRA and pattern of infarct on DWI / Frequency and count of MES and its relationship with multiple and borderzone infarction on DWI / Chapter 4.5 --- Discussion --- p.79 / Frequency of MES / Pattern of cerebral infarcts on DWI / Relationship between MES and multiple infarcts on DWI / References --- p.83 / Chapter Chapter Five / Chapter Chapter Five-I --- Novel Observations of the Characteristics of Real Time Genesis of Thromboembolism in Middle Cerebral Artery Stenosis Detected by Transcranial Doppler / Chapter 5.1.1 --- Abstract --- p.90 / Chapter 5.1.2 --- Introduction --- p.91 / Chapter 5.1.3 --- Methodology --- p.91 / Characteristics of patients / "MRA, DWI and conventional TCD data" / MES monitoring method and overall data / Neuroimaging and MES monitoring data in all five patients / Signal analysis in off-line / Confirmation test for the origin of MES / Chapter 5.1.4 --- Results --- p.104 / Frequency of three special phenomena / Characteristics of three special phenomena / Results of confirmation test for embolic source / Chapter 5.1.5 --- Discussion --- p.133 / Occurrence of MES with flow velocity change simultaneously / MES splatter / Bi-directional low frequency (S-velocity) vibration / Testing for source of MES detected from MCA stenosis / References --- p.139 / Chapter Chapter Five-II --- Characteristics of Microembolic Signals Detected near Its Origin from the Middle Cerebral Artery Stenosis / Chapter 5.2.1 --- Abstract --- p.143 / Chapter 5.2.2 --- Introduction --- p.144 / Chapter 5.2.3 --- Methodology --- p.144 / Patients / Microembolic signal (MES) detection / Classification of MES / Chapter 5.2.4 --- Results --- p.145 / Types of MES detected from MCA stenosis / Characteristics of three types of MES / Chapter 5.2.5 --- Discussion --- p.157 / Emboli moving from vessel wall to the center / Emboli vibration / About calculating the time delay between two channels / References --- p.160 / Chapter Chapter Five-III --- "Hemodynamic change,microembolic signal counts and use of antithrombotic treatments" / Chapter 5.3.1 --- Abstract --- p.163 / Chapter 5.3.2 --- Introduction --- p.164 / Chapter 5.3.3 --- Methodology --- p.164 / Chapter 5.3.4 --- Results / "The relationship among flow velocity, the number of MES and time since symptom onset" --- p.165 / Patient one / Patient two / Patient three / Chapter 5.3.5 --- Discussion / Association between flow velocity or MES change and different anticoagulants in acute stage / Progression of MCA stenosis after acute stage / Stability of MCA atherosclerotic stenosis / References --- p.173 / Chapter Chapter Six --- The Optimal Values of Flow Velocity on Transcranial Dopplerin Grading Severity of Middle Cerebral Artery Stenosis in Comparison With Magnetic Resonance Angiography / Chapter 6.1 --- Abstract --- p.179 / Chapter 6.2 --- Introduction --- p.180 / Chapter 6.3 --- Methodology --- p.180 / Patients / TCD examination / Grading of MCA stenosis on MRA / Statistical analysis / Chapter 6.4 --- Results --- p.182 / Detection of >50% MCA stenosis according to flow velocity / Grading severity of MCA stenosis by flow velocity / Chapter 6.5 --- Discussion --- p.186 / Reliability of TCD diagnosis for MCA stenosis / Grading MCA stenosis according to flow velocity on TCD / References / Abbreviations --- p.189 / Publications --- p.191

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Objective: Midlife obesity is a risk factor for dementia development. Obesity has also been linked to hyperaldosteronism, and this can be modeled in rats by high fat (HF) feeding from weaning. Aldosterone, or activation of the mineralocorticoid receptor (MR) causes cerebrovascular injury in lean hypertensive rats. We hypothesized that rats fed a HF diet would show inward middle cerebral artery (MCA) remodeling that could be prevented by MR antagonism. We further proposed that the cerebral artery remodeling would be associated with white mater injury. Methods: Three-week-old male Sprague-Dawley rats were fed a HF diet ± the MR antagonist canrenoic acid (Canr) for 17 weeks. Control rats received normal chow (control NC). MCA structure was assessed by pressure myography. Results: The MCAs from HF fed rats had smaller lumens and thicker walls when compared to arteries from control NC rats; Canr prevented the MCA remodeling associated with HF feeding. HF feeding increased the mRNA expression of markers of cell proliferation and vascular inflammation in cerebral arteries and Canr treatment prevented this. White mater injury was increased in the rats fed the HF diet and this was reduced by Canr treatment. The expression of doublecortin, a marker of new and immature neurons was reduced in HF fed rats, and MR antagonism normalized this. Conclusions: These data suggest that HF feeding leads to MR dependent remodeling of the MCA and this is associated with markers of dementia development.

<p>Stroke is the third leading cause of morbidity and mortality in the industrialized world. Subarachnoid hemorrhage (SAH), the least common form of stroke, is one of the most demanding diseases treated in neurointensive care units. Cerebral ischemia may develop rapidly, and has a major influence on outcome.To be able to save parts of the brain that are at risk for ischemic brain damage, there is a need for reliable monitoring techniques. Understanding the pathophysiology of cerebral ischemia is a prerequisite both for the correct treatment of these diseases and for the development of new monitoring techniques and treatment modalities. The main aim of this thesis was to gain insight into the mechanisms of cerebral ischemia by studying early hemodynamic and metabolic changes with positron emission tomography and neurochemical changes with microdialysis. A secondary aim was to evaluate the potential of these techniques for detecting ischemia and predicting the degree of reversibility of ischemic changes.</p><p>Early changes in cerebral blood flow (CBF) and metabolism (CMRO₂) were studied with repeated positron emission tomography in an experimental model (MCAO) of transient focal ischemia, and in SAH patients. CMRO₂ was superior to CBF in discriminating between tissue with irreversible damage and tissue with the potential for survival in the experimental model. A metabolic threshold of ischemia was found. Neurochemical changes in the ischemic regions were studied simultaneously with microdialysis. Extracellular concentrations of glucose, lactate, hypoxanthine, glutamate and glycerol were measured, and the lactate/pyruvate (LP) and lactate/glucose ratios were calculated. Changes in all the microdialysis parameters were related to the degree of ischemia (severe ischemia or penumbra). Especially the LP ratio and glycerol were found to be robust and specific markers of ischemia. In the patients, hemodynamic and metabolic changes were common, but diverse in the acute phase of SAH, and it was suggested that these changes may contribute to an increased vulnerability for secondary events and the development of secondary ischemic brain damage.</p>

Stroke is the third leading cause of morbidity and mortality in the industrialized world. Subarachnoid hemorrhage (SAH), the least common form of stroke, is one of the most demanding diseases treated in neurointensive care units. Cerebral ischemia may develop rapidly, and has a major influence on outcome.To be able to save parts of the brain that are at risk for ischemic brain damage, there is a need for reliable monitoring techniques. Understanding the pathophysiology of cerebral ischemia is a prerequisite both for the correct treatment of these diseases and for the development of new monitoring techniques and treatment modalities. The main aim of this thesis was to gain insight into the mechanisms of cerebral ischemia by studying early hemodynamic and metabolic changes with positron emission tomography and neurochemical changes with microdialysis. A secondary aim was to evaluate the potential of these techniques for detecting ischemia and predicting the degree of reversibility of ischemic changes. Early changes in cerebral blood flow (CBF) and metabolism (CMRO2) were studied with repeated positron emission tomography in an experimental model (MCAO) of transient focal ischemia, and in SAH patients. CMRO2 was superior to CBF in discriminating between tissue with irreversible damage and tissue with the potential for survival in the experimental model. A metabolic threshold of ischemia was found. Neurochemical changes in the ischemic regions were studied simultaneously with microdialysis. Extracellular concentrations of glucose, lactate, hypoxanthine, glutamate and glycerol were measured, and the lactate/pyruvate (LP) and lactate/glucose ratios were calculated. Changes in all the microdialysis parameters were related to the degree of ischemia (severe ischemia or penumbra). Especially the LP ratio and glycerol were found to be robust and specific markers of ischemia. In the patients, hemodynamic and metabolic changes were common, but diverse in the acute phase of SAH, and it was suggested that these changes may contribute to an increased vulnerability for secondary events and the development of secondary ischemic brain damage.

Sex steroids in general and estrogens in particular – in addition to their effects on the reproductive organs – affect a large number of crucial bodily functions, including “higher” brain functions. Neuropeptides constitute the phylogenetically oldest neurotransmitter system and are currently thought to act mainly during stress, disease or injury. The concentration of galanin is i.a. up-regulated by injury to the nervous system and by estrogen. The main focus of the present thesis was to investigate whether the reported neuroprotective effect of 17β-estradiol in experimental animal stroke models is partially mediated through its effects on galanin and if galanin per se exerts neuroprotective effects in stroke. An exploratory study of the effects of sex steroid concentrations due to gender and pubertal development showed differences in concentrations of i.a. the neuropeptides galanin and neuropeptide Y also in brain regions of female rats important for higher brain functions, including hippocampus and cortex, brain regions not directly involved in reproduction. Puberty brings about changes in several hormonal mechanisms, and our studies showed that the major effect on the concentrations of galanin in various brain regions of ovariectomized (ovx) rats, was brought about by 17β-estradiol. The pathophysiological mechanisms involved in thrombolysis – the current treatment of choice in human stroke – attempts the re-establishment of perfusion (reperfusion) to the lesioned area of the brain. This prompted us to develop a reperfusion stroke model in rats designed to be mild, focal and transient, allowing long-term observation periods of animals thriving well postoperatively. Mortality and morbidity during and after the middle cerebral artery (MCA) occlusion are important confounding factors crucial for the results. Changing anaesthesia from intraperitoneally administered chloral hydrate to isofl urane inhalation anaesthesia using endotracheal intubation and controlled ventilation markedly reduced the mortality rate from 25% to 10.6%, which was even further reduced down to 2.7 % by successively improved surgical skills. Contrary to our initial hypothesis, long-term 17β-estradiol treatment resulted in larger ischemic lesions in our stroke model compared to control treatment. After 3 days the cerebral ischemic lesion area was doubled after 17β-estradiol treatment in rats subjected to 60 min microclip occlusion of the MCA followed by reperfusion. A similar, but not statistically signifi cant difference was found after 7 and 14 days. Three groups studying different types of experimental animal stroke and different doses of 17β-estradiol treatment have recently also demonstrated lack of neuroprotection by 17β-estradiol treatment. Furthermore, large epidemiological clinical studies have recently also reported an increased risk and poorer outcome in postmenopausal women subjected to hormone replacement therapy. The concentrations of galanin-like immunoreactivity in extracts of punch biopsies from the penumbra area after transient MCA occlusion were found unchanged, but were decreased (p=0.015) in the apparently undamaged ipsilateral hippocampus. Galanin administered by continuous intracerebroventricular infusion (2.4 nmol/day) resulted in a 30% larger ischemic lesion compared to controls, measured 7 days after the MCA occlusion. Taken together, these results indicate that galanin in the brain is primarily a factor reacting to ischemic injury rather than a neuroprotective factor in its own right. Very limited information is available about the steady state serum concentrations of 17β-estradiol in response to different modes of administration to rats for days and weeks. The need for this information has become especially apparent during recent years due to the observable dichotomy of estrogens effects – neuroprotective or not – in the various animal models of brain ischemia reported in the current scientific literature. The cause of this dichotomy is likely to be found in the experimental setup, including the mode of administration of 17β-estradiol. Delayed steady state of serum 17β-estradiol concentrations were found when comparing two common modes of exogenous administration of 17β-estradiol – slow-release osmotic pumps vs. daily subcutaneously injections of 17β-estradiol solved in sesame oil – to ovx rats during 2 times 6 weeks crossover treatment. Steady state was reached at week 4 in the daily injections group compared to at week 6 in the slow release osmotic pumps group. Once steady state was reached, the concentration was the same in both groups for the reminder of the experiment (in total 12 weeks). / On the day of the public defence of the doctoral thesis, the status of article V was: Available on line since 24th of May 2005.

Background Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains. Methods We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability. Results The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method. Conclusions The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality. / <p>Funding Agencies|County Council of Ostergotland, Sweden||</p>

Many populations have low intakes of n-3 fatty acids, yet there is substantial evidence that the long chain n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3), found at high concentrations in the brain, is required for the proper development of the nervous system. However, less is known about requirements of long chain n-3 fatty acids for maintenance and function of the nervous system in later life. Several recent studies have reported that high amounts of long chain n-3 fatty acids reduce the extent of brain damage caused by cerebral ischemia in animals. However, whether or not a dietary deficiency of n-3 fatty acids increases the extent of injury when cerebral ischemia occurs has not been previously reported. The present studies, therefore, sought to determine if a diet deficient in n-3 fatty acids influences the extent of brain injury in the rat following cerebral ischemia. Male rats were fed an n-3 fatty acid adequate (control), an n-3 fatty acid deficient, or a high DHA diet for 5 weeks from weaning. Middle cerebral artery occlusion (MCAO) was induced and infarct volume was measured by 2,3,5,-triphenyltetrazolium chloride staining 24 hours after the procedure. Brain and platelet fatty acids were analyzed by gas liquid chromatography. DHA (22:6n-3) was 21-28% lower in brain phospholipids, and 17% lower in brain total fatty acids in the n-3 fatty acid deficient compared to control group, while 22:6n-3 was 12% higher in total brain fatty acids in the high DHA group than the control group. There was no significant difference in infarct volume (203, 220 and 218 mm³) among the control, n-3 fatty acid deficient, and high DHA groups, respectively. Platelet fatty acids and platelet aggregation were assessed to determine if these were influenced by the high DHA diet, and could possibly explain the observation of an apparent, but not statistically significant, higher number of rats with hemorrhages in the high DHA diet group. Platelet lipid arachidonic acid was not lower and platelet aggregation, assessed ex vivo using whole blood with a platelet function analyzer, was not longer in rats fed the high DHA compared to control or n-3 fatty acid deficient diets. In summary, dietary n-3 fatty acid deficiency did not increase the extent of brain injury following cerebral ischemia. The possibility that high dietary 22:6n-3 might increase susceptibility to cerebral hemorrhage will require further study.

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Thesis (Ph. D.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains x, 121 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 84-118).