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>

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21649号 / 医博第4455号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 宮本 享, 教授 森田 智視, 教授 鈴木 実 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>UVOD: Ateroskleroza je najče&scaron;ća bolest karotidnih arterija i uzrok je oko 20% svih ishemijskih moždanih udara (IMU). Osim stepena stenoze i određene karakteristike karotidnog plaka označavaju povi&scaron;en rizik za IMU. Ultrazvukom je moguće pouzdano evaluirati aterosklerotske promene na karotidnim arterijama. Iako su faktori rizika (FR) za aterosklerozu istovremeno i FR za IMU, prisustvo identičnih FR kod pacijenata sa IMU, ne znači i prisustvo istog stepena ateroskleroze na karotidnim arterijama. CILJ: Utvrđivanje povezanosti pojedinih ultrazvučnih karakteristika karotidne ateroskleroze, sa prisustvom različitih kardiometaboličkih FR i njihovih biomarkera, kod pacijenata sa IMU. MATERIJAL I METODE: U istraživanje je uključeno 120 pacijenata sa nekardioembolijskim IMU u karotidnom slivu koji su podeljeni u dve grupe; 60 sa lakunarnim i 60 sa nelakunarnim infarktom mozga. Svim pacijentima je određivano prisustvo FR, kao &scaron;to su hipertenzija, dijabetes, hiperlipoproteinemija, pu&scaron;enje, gojaznost, metabolički sindrom, hiperhomocisteinemija i inflamacija. Beležene su vrednosti krvnog pritiska, glikemije, glikoliziranog hemoglobina, parametara lipidskog statusa, apolipoproteina (Apo) A-I i B, lipoproteina a, indeksa telesne mase (BMI), homocisteina, C reaktivnog proteina (CRP). Pomoću karotidnog dupleks ultrazvuka određivane su vrednosti intima-medijalnog zadebljanja (IMT), morfologija plaka, povr&scaron;ina plaka, stepen stenoze. Demografske karakteristike, FR i njihovi biomarkeri, te ultrazvučne karakteristike karotidne ateroskleroze, poređene su između dve grupe pacijenata. Kori&scaron;ćeni su hi-kvadrat test i t-test. Korelacije FR i vrednosti njihovih biomarkera sa različitim karakteristikama karotidnog plaka, određivane su upotrebom Pearsonovog koeficijenta korelacije r i Kramerovog V. Upotrebom regresionih analiza ispitivan je prediktivni značaj određenih FR i njihovih biomarkera u pojavi pojedinih karakteristika karotidnog plaka. REZULTATI: Vi&scaron;e pacijenata sa lakunarnim infarktom je imalo hipertenziju (98.3% naspram 85%; p=0.021). Pacijenti sa lakunarnim infarktom imali su veće vrednosti BMI (27.6 kg/m2 naspram 25.9 kg/m2; p=0.029), dok su pacijenti sa nelakunarnim infarktom imali veće vrednosti CRP (16.4 mg/l naspram 6.8 mg/l; p=0.001). Demografske karakteristike, ostali FR i njihovi biomarkeri, kao i vrednosti karotidnog IMT se nisu značajno razlikovali između dve grupe pacijenata. Pacijenti sa nelakunarnim infarktom su imali veći stepen karotidne stenoze (79.7% naspram 33.2%; p=0,0001), kao i če&scaron;će prisustvo heterogenog plaka (73.3% naspram 35%; p&lt;0,001), hipoehogenog plaka (51.7% naspram 16.7%; p&lt;0.001) i neravnog plaka (81.7% naspram 21.7%; p&lt;0,001). Sa vrednostima IMT značajno (p&lt;0.05) su korelirali životna dob pacijenata (r=0.276), dijabetes (Cramerovo V=0.236), metabolički sindrom (Cramerovo V=0.247), HDL holesterol (r=-0.254), LDL/HDL (r=0.306), ApoA-I (r=-0.386) i ApoB/ApoA-I (r=0.359). Sa prisustvom heterogenog plaka su korelirali metabolički sindrom (Cramerovo V=0.246), ApoB (r=0.213), ApoB/ApoA-I (r=0.207) i povi&scaron;en CRP (Cramerovo V=0.266). Sa neravnom povr&scaron;inom plaka značajno je korelirao povi&scaron;en CRP (Cramerovo V=0.283). Sa stepenom stenoze značajno su korelirali BMI (r=-0.180) i povi&scaron;en CRP (Cramerovo V=0.301). Nezavisni prediktori povi&scaron;enih vrednosti IMT bili su starija životna dob pacijenata (&beta;=0.230; p=0.006), ApoA-I (&beta;=-0.244; p=0.008) i ApoB/ApoA-I (&beta;=0.247; p=0.007). Prediktori prisustva heterogenog plaka bili su mu&scaron;ki pol (p=0.011; OR=3.425), ApoB (p=0.007; OR=8.972), BMI (p=0.0001; OR=0.380), metabolički sindrom (p=0.003; OR=4.555) i povi&scaron;en CRP (p=0.018; OR=2.800). Prediktori prisustva hipoehogenog plaka bili su ApoB (p&lt;0.001; OR=29.2), BMI (p=0.02; OR=0.514), metabolički sindrom (p&lt;0.001; OR=9.224) i povi&scaron;en CRP (p=0.046; OR=2.659). Povi&scaron;en CRP bio je jedini prediktor prisustva neravnog plaka (p=0.002; OR=3.203), kao i prisustva većeg stepene karotidne stenoze (&beta;=0.270; p=0.002). ZAKLJUČAK: Iako je karotidna stenoza znatno zastupljenija među pacijenatima sa nelakunarnim nego lakunarnim nekardioembolijskim IMU, prisustvo kardiometaboličkih FR, njihovih biomarkera i vrednosti IMT se bitno ne razlikuje između ove dve grupe pacijenata. Osim stenoze i prisustvo heterogenog, hipoehogenog i neravnog karotidnog plaka nosi povi&scaron;en rizik za IMU. Među FR i njihovim biomarkerima ApoA-I i ApoB su najbolji prediktori karotidne ateroskleroze. Apolipoprotein B i metabolički sindrom su najjače povezani sa prisustvom heterogenog i hipoehogenog plaka. Povi&scaron;en CRP kod pacijenata sa akutnim IMU može biti znak destabilizacije plaka i ukazivati na prisustvo signifikantne karotidne stenoze.</p> / <p>INTRODUCTION: Atherosclerosis is the most common disease of carotid arteries, causing 20% of all ischemic strokes. Besides the degree of stenosis, certain characteristics of carotid plaques indicate an increased risk for stroke. Carotid ultrasound can reliably evaluate atherosclerotic changes in carotid arteries. Although the risk factors for atherosclerosis are the same as the risk factors for stroke, the presence of identical risk factors in patients with stroke does not necessarily mean the presence of the same degree of carotid atherosclerosis. AIM: To determine correlation of certain characteristics of carotid atherosclerosis detected by ultrasound with the presence of various cardiometabolic risk factors in patients with ischemic stroke. METHODS: The study included 120 patients with noncardioembolic ischemic stroke in the anterior circulation, who were divided into two groups; 60 with lacunar and 60 with nonlacunar brain infarction. The presence of cardiometabolic risk factors, such as hypertension, diabetes, hyperlipoproteinemia, smoking, obesity, metabolic syndrome, hyperhomocysteinemia, and inflammation, was evaluated in all patients. Data regarding blood pressure, glycemia, glycated hemoglobin, lipid status parameters, apolipoprotein (ApoAI and ApoB), lipoprotein a, body mass index (BMI), homocysteine, and C-reactive protein (CRP) were collected. Intima-media thickness (IMT), carotid plaque characteristics (morphology, surface) and the degree of stenosis were determined by carotid duplex ultrasound. Demographic characteristics, risk factors, biomarkers, as well as ultrasound characteristics of carotid atherosclerosis, were compared between patients with lacunar and nonlacunar stroke. Two-sample student t-test and &chi;2 test were used for comparisons. In order to assess the correlation of various risk factors and their biomarkers with different characteristics of carotid plaques, we used the Pearson correlation coefficient r and Cramer&#39;s V. Regression analysis was used to evaluate the association of risk factors and their biomarkers with various carotid atherosclerosis characteristics. RESULTS: More patients with lacunar stroke had hypertension (98.3% vs. 85%; p=0.021). Patients with lacunar stroke had higher BMI values (27.6 kg/m2 vs. 25.9 kg/m2; p=0.029), while patients with nonlacunar stroke had higher CRP values (16.4 mg/l vs. 6.8 mg/l; p=0.001). Demographic characteristics, other risk factors and their biomarkers, as well as carotid IMT were not significantly different between the two groups of patients. Patients with nonlacunar stroke had a higher degree of carotid stenosis (79.7% vs. 33.2%; p=0.0001) and a higher prevalence of heterogeneous plaques (73.3% vs. 35%; p&lt;0.001), hypoechogenic plaques (51.7% vs. 16.7%; p&lt;0.001), and plaques with irregular surface (81.7% vs. 21.7%; p&lt;0,001). IMT was significantly (p&lt;0.05) correlated with the age of patients (r=0.276), diabetes (Cramer&rsquo;s V=0.236), metabolic syndrome (Cramer&rsquo;s V=0.247), HDL cholesterol (r=-0.254), LDL/HDL (r=0.306), ApoA-I (r=-0.386) and ApoB/ApoA-I (r=0.359). The presence of a heterogeneous plaque was correlated with metabolic syndrome (Cramer&rsquo;s V=0.246) ApoB (r=0.213), ApoB/ApoA-I (r=0.207) and elevated CRP (Cramer&rsquo;s V=0.266). A plaque with irregular surface was correlated with elevated CRP (Cramer&rsquo;s V=0.283). The degree of carotid stenosis was correlated with BMI (r=-0.180) and elevated CRP (Cramer&rsquo;s V=0.301). The independent predictors of higher values of IMT were older age (&beta;=0.230; p=0.006), ApoA-I (&beta;=-0.244; p=0.008), and ApoB/ApoA-I (&beta;=0.247; p=0.007). The predictors of the presence of a heterogeneous plaque were male gender (p=0.011; OR=3.425), ApoB (p=0.007; OR=8.972), BMI (p=0.0001; OR=0.380), metabolic syndrome (p=0.003; OR=4.555) and elevated CRP (p=0.018; OR=2.800). The predictors of the presence of a hypoechogenic plaque were ApoB (p&lt;0.001; OR=29.2), BMI (p=0.02; OR=0.514), metabolic syndrome (p&lt;0.001; OR=9.224) and elevated CRP (p=0.046; OR=2.659). Elevated CRP was the only independent predictor of a plaque with irregular surface (p=0.002; OR=3.203) and of a higher degree of carotid stenosis (&beta;=0.270; p=0.002). CONCULSIONS: Although carotid stenosis is significantly more pronounced in patients with nonlacunar than those with lacunar noncardioembolic ischemic stroke, cardiometabolic risk factors, their biomarkers and carotid IMT do not differ significantly between the two groups of patients. In addition to stenosis, a presence of heterogeneous, hypoechogenic and irregular-surface carotid plaques indicates an increased risk for ischemic nonlacunar stroke. Among the cardiometabolic risk factors and their biomarkers, ApoAI and ApoB have the strongest association with carotid atherosclerosis. Apolipoprotein B and metabolic syndrome have the strongest association with a heterogeneous and hypoechogenic carotid plaque. Elevated CRP in patients with acute ischemic stroke may be a sign of carotid plaque destabilization and can indicate a significant carotid stenosis.</p>

Introdução e Objetivos: A craniectomia descompressiva com duroplastia (CDD) reduz a mortalidade e melhora o prognóstico funcional em doentes com acidente vascular encefálico isquêmico (AVEi) hemisférico e proporciona a redução da pressão intracraniana. Entretanto, pouco se sabe sobre sua repercussão na hemodinâmica cerebral. O objetivo do presente trabalho é o de avaliar com a tomografia computadorizada com estudo de perfusão (TCP) as alterações hemodinâmicas nos doentes com AVEi após a CDD e identificar possíveis marcadores prognósticos substitutos. Métodos: Foram avaliados 27 doentes com AVEi com indicação de CDD. Os parâmetros hemodinâmicos da TCP estudados no período pré-operatório e em até 24h após a cirurgia foram: duração média de trânsito (DMT), volume sanguíneo encefálico (VSE) e fluxo sanguíneo encefálico (FSE). O desfecho primário utilizado foi a melhora ou a ausência de melhora hemodinâmica. Os desfechos secundários foram a escala de Rankin modificada em seis meses, dicotomizada como favorável (0-3) ou desfavorável (4-6); casos fatais em um mês e em seis meses. Resultados: 18 (70,3%) doentes eram do sexo feminino e 12 (44,4%) tinham idade superior a 55 anos. Houve melhora da DMT (queda de 8,74 para 8,24, p=0,01) e tendência a melhora do FSE (aumento de 22,37 para 25,26, p=0,06) após a CDD. Não houve diferença estatística em relação ao VSC (aumento de 2,14 para 2,26, p=0,33). A idade superior a 55 anos foi o preditor independente de prognóstico desfavorável (p=0,03) e a DMT pré-operatória, foi preditora hemodinâmica para mortalidade em seis meses (8,20 vs 9,23, p=0,04). Conclusões: A craniectomia descompressiva com expansão dural determinou melhora hemodinâmica na maioria dos doentes com AVEi hemisférico. A DTM préoperatória é um bom marcador substituto para a possibilidade de óbito em seis meses / Background and Objectives: Decompressive craniectomy (DC) reduces the mortality and improves the functional outcome in patients with malignant cerebral infarction (MCI). This procedure causes a decrease of the intracranial pressure, however, little is known about its impact in brain hemodynamics. Therefore, our goal is to study through CT perfusion the hemodynamics changes that may occur in patients with MCI after the DC. Methods: 27 patients with MCI treated with DC were studied. The CT perfusion hemodynamic parameters - the mean transit time (MTT), the cerebral blood volume (CBV) and cerebral blood flow (CBF) - were evaluated preoperatively and within the first 24 hours after the DC. The primary outcome measure was improvement or lack of improvement in cerebral hemodynamics. Secondary outcomes were the modified Rankin scale in 6 months, classified as favorable (0-3) and unfavorable (4-6); and, fatal cases at 1 month and 6 months. Results: 18 (70.3%) patients were female and 12 (44.4%) were older than 55 years. There was improvement of MTT (decrease from 8.74 to 8.24, p = 0.01) and a trend towards improvement of the CBF (increase from 22.37 to 25.26, p = 0.06) after DC. There was no statistical difference in the CBV before and after DC (increase from 2.14 to 2.26, p = 0.33). Patients over 55 years had poorer prognosis (p=0.03) and preoperative MTT was an independent hemodynamic predictor of mortality at 6 months (8.20 vs 9.23, p=0.04). Conclusions: DC improved cerebral hemodynamics in most patients with malignant ischemic stroke. Preoperative MTT seems to be a good marker for case fatality in 6 months

Introdução e Objetivos: A craniectomia descompressiva com duroplastia (CDD) reduz a mortalidade e melhora o prognóstico funcional em doentes com acidente vascular encefálico isquêmico (AVEi) hemisférico e proporciona a redução da pressão intracraniana. Entretanto, pouco se sabe sobre sua repercussão na hemodinâmica cerebral. O objetivo do presente trabalho é o de avaliar com a tomografia computadorizada com estudo de perfusão (TCP) as alterações hemodinâmicas nos doentes com AVEi após a CDD e identificar possíveis marcadores prognósticos substitutos. Métodos: Foram avaliados 27 doentes com AVEi com indicação de CDD. Os parâmetros hemodinâmicos da TCP estudados no período pré-operatório e em até 24h após a cirurgia foram: duração média de trânsito (DMT), volume sanguíneo encefálico (VSE) e fluxo sanguíneo encefálico (FSE). O desfecho primário utilizado foi a melhora ou a ausência de melhora hemodinâmica. Os desfechos secundários foram a escala de Rankin modificada em seis meses, dicotomizada como favorável (0-3) ou desfavorável (4-6); casos fatais em um mês e em seis meses. Resultados: 18 (70,3%) doentes eram do sexo feminino e 12 (44,4%) tinham idade superior a 55 anos. Houve melhora da DMT (queda de 8,74 para 8,24, p=0,01) e tendência a melhora do FSE (aumento de 22,37 para 25,26, p=0,06) após a CDD. Não houve diferença estatística em relação ao VSC (aumento de 2,14 para 2,26, p=0,33). A idade superior a 55 anos foi o preditor independente de prognóstico desfavorável (p=0,03) e a DMT pré-operatória, foi preditora hemodinâmica para mortalidade em seis meses (8,20 vs 9,23, p=0,04). Conclusões: A craniectomia descompressiva com expansão dural determinou melhora hemodinâmica na maioria dos doentes com AVEi hemisférico. A DTM préoperatória é um bom marcador substituto para a possibilidade de óbito em seis meses / Background and Objectives: Decompressive craniectomy (DC) reduces the mortality and improves the functional outcome in patients with malignant cerebral infarction (MCI). This procedure causes a decrease of the intracranial pressure, however, little is known about its impact in brain hemodynamics. Therefore, our goal is to study through CT perfusion the hemodynamics changes that may occur in patients with MCI after the DC. Methods: 27 patients with MCI treated with DC were studied. The CT perfusion hemodynamic parameters - the mean transit time (MTT), the cerebral blood volume (CBV) and cerebral blood flow (CBF) - were evaluated preoperatively and within the first 24 hours after the DC. The primary outcome measure was improvement or lack of improvement in cerebral hemodynamics. Secondary outcomes were the modified Rankin scale in 6 months, classified as favorable (0-3) and unfavorable (4-6); and, fatal cases at 1 month and 6 months. Results: 18 (70.3%) patients were female and 12 (44.4%) were older than 55 years. There was improvement of MTT (decrease from 8.74 to 8.24, p = 0.01) and a trend towards improvement of the CBF (increase from 22.37 to 25.26, p = 0.06) after DC. There was no statistical difference in the CBV before and after DC (increase from 2.14 to 2.26, p = 0.33). Patients over 55 years had poorer prognosis (p=0.03) and preoperative MTT was an independent hemodynamic predictor of mortality at 6 months (8.20 vs 9.23, p=0.04). Conclusions: DC improved cerebral hemodynamics in most patients with malignant ischemic stroke. Preoperative MTT seems to be a good marker for case fatality in 6 months

Abstract There is a lack of reliable methods of evaluation of brain ischemic injury in patients undergoing cardiac surgery. The present study was, therefore, planned to evaluate whether serum S100β protein (I), brain cortical microdialysis (II), intracranial pressure (III) and electroencephalography (EEG) (IV) are predictive of postoperative death and brain ischemic injury in an experimental surviving porcine model of hypothermic circulatory arrest (HCA). One hundred and twenty eight (128) female, juvenile (8 to 10 weeks of age) pigs of native stock, weighing 21.0 to 38.2 kg, underwent cardio-pulmonary bypass prior to, and following, a 75-minute period of HCA at a brain temperature of 18°C. During the operation, hemodynamic, electrocardiograph and temperature monitoring was performed continuously. Furthermore, metabolic parameters were monitored at baseline, end of cooling, at intervals of two, four and eight hours after HCA and before extubation. Electroencephalographic recording was performed in all animals, serum S100β protein measurement in 18 animals, cortical microdialysis in 109 animals, and intracranial pressure monitoring in 58 animals. After the operation, assessment of behavior was made on a daily basis until death or elective sacrifice on the seventh postoperative day. All four studies showed that these parameters were predictive of postoperative outcome. Animals with severe histopathological injury had higher serum S100β protein levels at every time interval after HCA. Analysis of cortical brain microdialysis showed that the lactate/glucose ratio was significantly lower and the brain glucose concentration significantly higher among survivors during the early postoperative hours. Intracranial pressure increased significantly after 75 minutes of HCA, and this was associated with a significantly increased risk of postoperative death and brain infarction. A slower recovery of EEG burst percentage after HCA was significantly associated with the development of severe cerebral cortex, brain stem and cerebellum ischemic injury. In conclusion, serum S100β protein proved to be a reliable marker of brain ischemic injury as assessed on histopathological examination. Cerebral microdialysis is a useful method of cerebral monitoring during experimental HCA. Low brain glucose concentrations and high brain lactate/ glucose ratios after HCA are strong predictors of postoperative death. Increased intracranial pressure severely affected the postoperative outcome and may be a potential target for treatment. EEG burst percentage as a sum effect of anesthetic agent and ischemic brain damage is a useful tool for early prediction of severe brain damage after HCA. Among these monitoring methods, brain cortical microdialysis seems to be the most powerful one in predicting brain injury after experimental hypothermic circulatory arrest.

Abstract Increased plasma cholesterol is a well-known risk factor for cardiovascular diseases in middle and early old age. At older ages, this association seems to disappear. Very few studies have assessed the impact of the lifelong cholesterol burden on old age, the purpose of this thesis. Study populations consisted of 1) old persons with familial hypercholesterolemia (FH), a genetic disorder associated with an increased risk of coronary heart disease (CHD) if untreated, and 2) initially healthy men (The Helsinki Businessmen Study, HBS) followed-up from midlife to old age. A population-based FH cohort, aged&#160;&#8805;&#160;65 years (n=37, aged 65 to 84 years) agreed to participate in this study. All but one of them had been using statin therapy for approx. 15 years. Variables studied were: health-related quality of life (HRQoL) with questionnaires (RAND-36, 15D), a brain magnetic resonance imaging (MRI) scan and cognitive tests (CERAD). These older FH patients enjoyed a similar HRQoL as controls in the general population. Only two (6%) of the older FH patients had clinically silent brain infarcts detected by MRI and those aged 65 to 74 years did not have more white matter hyperintensities (WMHIs) when compared to middle-aged controls. In the cognitive assessments, FH patients, especially those with duration of statin therapy longer than median, even expressed better episodic memory than population controls. HBS consists of a cohort of men (3277 men) who at baseline (1964–1973) were healthy and in their 40s. They were subdivided into seven groups according to baseline total cholesterol value at 1 mmol/L intervals starting from &#8804; &#160;4 mmol/L. In 2000, at a mean age of 73 years, they filled a postal questionnaire including RAND-36. Cumulative mortality data were collected up to January 2010. A strong and graded relation was found between the cholesterol level and total mortality, those men with a cholesterol level &#8804; &#160;4 mmol/L exhibiting the lowest mortality. A low cholesterol value at midlife also predicted a better score in the Physical functioning scale of RAND-36 in old age. In conclusion, in initially healthy men, a low cholesterol value at midlife was associated with better survival and better physical function in old age. Despite their genetic risk, FH patients on long-term statin medication seemed to enjoy a health and cognitive status similar to the general population. / Tiivistelmä Suurentunut plasman kolesterolipitoisuus on tunnettu valtimotautien riskitekijä keski-iässä, mutta vanhuusiässä kolesterolin merkitys näyttää vähentyvän. Hyvin harvassa tutkimuksessa on tutkittu elämänaikaisen kolesterolitason vaikutuksia vanhuusiän terveydentilaan, kuten tässä väitöskirjatyössä. Tutkimuskohteina olivat 1) iäkkäät, joilla on familiaalinen hyperkolesterolemia (FH) eli perinnöllinen sairaus, johon hoitamattomana liittyy lisääntynyt sepelvaltimotaudin riski, sekä 2) alun perin terveet miehet (Helsingin Johtajatutkimus), joita seurattiin keski-iästä vanhuuteen. Väestöpohjainen, 65 vuotta täyttänyt (65–84 vuotta, 37 henkilöä) FH-potilaiden ryhmä oli yhtä lukuun ottamatta käyttänyt keskimäärin 15 vuoden ajan statiinilääkitystä. Heille tehtiin seuraavat tutkimukset: terveyteen liittyvän elämänlaadun kyselyt (RAND-36- ja15D-mittarit), aivojen magneettitutkimus (MRI) ja kognitiota tutkivat testit (CERAD). FH-potilaiden elämänlaatu ei eronnut väestöverrokeista. Aivojen MRI tutkimuksessa vain kahdella (6&#160;%) FH-potilaalla oli todettavissa kliinisesti hiljainen aivoinfarkti ja 65–74-vuotiailla FH-potilailla ei ollut enempää valkean aineen muutoksia kuin keski-ikäisillä verrokeilla. Kognitiotutkimuksissa FH-potilailla oli parempi episodinen muisti kuin väestöverrokeilla, etenkin niillä FH-potilailla, joiden statiinihoidon kesto oli mediaania pidempi. Helsingin Johtajatutkimukseen kuului alun perin 3 277 lähtötilanteessa (1964–1973) tervettä keski-ikäistä miestä. Heidät jaettiin lähtövaiheen kolesterolitason perusteella seitsemään ryhmään yhden millimoolin välein siten, että alin ryhmä oli alle 4 mmol/l. Vuonna 2000 (keski-ikä 73 vuotta) lähetettiin postikysely, johon kuului myös RAND-36. Kokonaiskuolleisuutta seurattiin tammikuuhun 2010 asti. Kokonaiskuolleisuuden ja keski-iän kokonaiskolesterolin välillä oli vahva ja asteittainen suhde siten, että niillä miehillä oli pienin kuolleisuus, joilla oli alin kolesteroli (alle 4 mmol/l). Pienin kolesterolipitoisuus keski-iässä oli myös yhteydessä RAND-36-mittarin Fyysinen toimintakyky -osion parempaan pistemäärään. Yhteenveto: Alun perin terveillä miehillä pieni kolesterolipitoisuus keski-iässä ennusti pitempää elämää ja myös parempaa fyysisistä toimintakykyä vanhalla iällä. Huolimatta perinnöllisestä riskistä oli pitkäaikaista statiinilääkitystä käyttäneiden FH-potilaiden terveydentila muuta väestöä vastaava.

Diese Schrift faßt in zwei Abschnitten eigene Beiträge zur Einführung der lokalisierten Magnetresonanzspektroskopie (MRS) und der funktionellen Magnetresonanztomografie (fMRT) in die diagnostische Medizin zusammen. Im ersten Teil wird beschrieben, wie die biochemischen Metabolite N-Azetylaspartat, Kreatin und Phosphokreatin, cholin-enthaltende Verbindungen und Laktat durch die Einführung der stimulierten Echo-Akquisitionsmethode (STEAM) als Lokalisationstechnik in die diagnostische Magnetresonanzspektroskopie in definierten Hirnregionen gesunder Versuchspersonen nichtinvasiv zugänglich gemacht und erstmals in Form von In-vivo-Konzentrationen quantifiziert werden konnten. Daraufhin wird gezeigt, wie die Weiterentwicklung der robusten STEAM-Technik zu kurzen Echozeiten das Signal-zu-Rauschverhältnis und damit die Messung kleinerer Untersuchungsvolumina erheblich verbesserte. Zudem wurde dadurch die Erkennung und Quantifizierung weiterer Metabolite wie z. B. des myo- und scyllo-Inosits, des Glutamats und Glutamins, des N-Azetylaspartylglutamats und der Glukose ermöglicht. Diese Methode setzte damit zusammen mit der verwendeten linearen Kombinationsmethode (LCModel) zur Konzentrationsbestimmung den spektralen Qualitätsstandard des gesamten letzten Jahrzehnts. Ferner werden die parallelen Pionierarbeiten zu Hirnerkrankungen fokaler und generalisierter Art beleuchtet. Diese Anwendungen der lokalisierten STEAM-Protonenspektroskopie in Einzelvolumentechnik zur Messung umschriebener Prozesse umfassen zerebrale Tumore und Infarkte, Plaques der multiplen Sklerose sowie andere entzündliche und degenerative Läsionen. Auch die lokalisierte STEAM-Phosphorspektroskopie und nichtzerebrale Anwendungen wie die lokalisierte Protonenspektroskopie von Faserbündeln des Skelettmuskels und der Niere bauen weitgehend auf diesem Fortschritt in der Methode auf. Zusätzlich werden Anwendungen bei generalisierten Erkrankungen gestreift, speziell angeborenen Stoffwechselerkrankungen des Kindesalters wie mitochondrialen und lysosomalen Defekten, Stoffwechselentgleisungen bei Diabetes mellitus und Leberzirrhose, psychiatrischen Erkrankungen wie der Alzheimer-Demenz. Die weitere Verbreitung dieser Erkenntnisse in die klinische Diagnostik wird entscheidend von der Beachtung des hier eingeführten Qualitätsmaßstabs und der darauf aufbauenden absoluten Metabolitquantifizierung abhängen. Der zweite Teil dieser Arbeit faßt ausgehend von funktionellen protonenspektroskopischen Untersuchungen des visuellen Kortex bei photischer Aktivierung Fortschritte zusammen, die bei der Entwicklung und Anwendung der suszeptibilitätsempfindlichen MR-Tomografie zur Messung physiologischer Hirnaktivierung mit dem Modell der visuellen Stimulation erzielt wurden. Während die Belastung des Energiestoffwechsels im angeregten striatären Kortex anhand abgesunkener Gewebespiegel von Glukose und angestiegener Laktatkonzentrationen mithilfe der zeitaufgelösten Spektroskopie beobachtet werden konnte, gelang die Demarkierung der Ausdehnung der Hirngewebeaktivierung mithilfe der T2*-gewichteten FLASH-MRT, die begleitende Verminderungen des paramagnetischen Desoxyhämoglobins im funktionell aktiven Gewebe mit Anstiegen der Bildsignalintensität wiedergibt. Schließlich werden Untersuchungen beschrieben, die die Empfindlichkeit dieses endogenen, sauerstoffspiegelabhängigen Suszeptibilitätskontrastes für die Wirkung verschiedener Medikamente bzw. pharmakologischer Stimulantien zeigen, die direkt oder indirekt über bestimmte vaskuläre Rezeptoren wirken. Diese Untersuchungen befördern wiederum ein neues Gebiet der Bildgebung, die pharmakologische MRT. / This work has two main parts that summarize pioneering contributions to localized magnetic resonance spectroscopy (MRS), functional magnetic resonance tomography (fMRI), and the introduction of these modalities into diagnostic medicine. First, it is described how biochemical metabolites such as the intracellular pools of N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, and lactate have been made accessible to noninvasive detection and to the quantification of their respective concentrations in vivo in defined cerebral regions of healthy subjects by utilizing the stimulated echo-acquisition mode (STEAM) localization technique. Then it is shown that further development of the robust STEAM technique to short echo times not only increased the signal-to-noise of the measurement, thereby providing access to smaller volumes-of-interest, but also allowed for the detection and quantification of additional metabolites such as myo- and scyllo-inositol, glutamate, glutamine, N-acetylaspartylglutamate, and glucose. Thus, together with the adoption of the linear combination method (LCModel) for concentration calculation, this method has set the standard for spectroscopic state-of-the-art in the field well over the last decade. Moreover, pioneering achievements have been highlighted with regard to applications in brain diseases of focal and generalized nature. Pertinent applications of localized single-volume STEAM proton spectroscopy to circumscribed processes include cerebral tumors, cerebral infarction, multiple sclerosis plaques, and other inflammatory and degenerative lesions. Also localized STEAM phosphorus spectroscopy and non-cerebral applications including localized proton spectroscopy of skeletal muscle and kidney largely depend on the short-echo time STEAM technique. In addition, applications in generalized disorders have been explored, which include inborn errors of metabolism in childhood, such as mitochondrial and lysosomal defects, metabolic disturbances in diabetes mellitus and liver cirrhosis, and psychiatric diseases such as Alzheimer's dementia. The further utilization of these novel methods in clinical diagnostics will heavily depend on quality measures and the mastering of a true quantification procedure as demonstrated. Second, this work summarizes achievements made in developing and applying both proton MR spectroscopy and susceptibility-sensitized MR imaging to measure physiologic brain activation using visual stimulation as a model. Whereas metabolic stress, brought upon the bioenergetic steady state in the responding striate cortex, was detected by decreased parenchymal glucose and increased lactate using time-resolved spectroscopy, mapping the extent of parenchymal activation was found to be possible by increases of image intensity in T2*-weighted FLASH MRI made sensitive to concomitant decreases of paramagnetic deoxyhemoglobin in the functionally active tissue. Finally, studies are described, which show the sensitivity of this endogenous, susceptibility-sensitive contrast, now generally known as BOLD effect, to various drugs or pharmacologic stimuli acting either directly or indirectly on vascular receptors. These latter studies open up again a new field of imaging, dubbed pharmacologic MRI.

Dissertation (Ph.D.)--University of South Florida, 2007. / Includes vita. Includes bibliographical references. Also available online.

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 187 pages. Includes vita. Includes bibliographical references.