Diss. Stockholm : Karol. inst.

Cerebral Cavernous Malformations (CCM) and Intracranial Aneurysms (IA) are cerebrovascular disorders that can lead to a hemorrhagic stroke and other neurological problems. CCMs are characterized by abnormally enlarged capillary cavities while IAs are saccular outpouchings of intracranial arteries. CCM is found in approximately 0.4% to 0.9% of the population, while IA is more common (3-6%). / This dissertation aimed to add to the body of research for CCM and IA and was divided into two parts. Initial work focused on the characterization and identification of the genes involved in CCM; the second phase focused on the identification of a susceptibility gene for IA. / In the first phase, the CCM1, CCM2 and CCM3 genes were characterized in families and in sporadic cases of CCM. In both cohorts, a causative mutation was identified in 71% of the cases. Subsequent MLPA analysis of subjects with no CCM mutations revealed that large genomic deletions and duplications are a common cause of CCM. In addition, investigation of CCM1 point mutations revealed that these were not simple missense mutations but that they rather activated cryptic splice-donor sites and caused aberrant splicing. Furthermore, the genetic predisposition to CCM in sporadic cases with a single lesion was determined to be different from sporadic cases with multiple malformations. Investigation into the loss of heterozygosity demonstrated a plausible mechanism for CCM pathogenesis involving a second somatic hit at the site of the lesion, suggesting that CCM may be caused by a complete loss of CCM protein function. / In the second phase, a genome-wide scan of a large family and subsequent linkage analysis using a monogenic approach identified a susceptibility locus for IA (ANIB4). / As a result of this research, we have greatly contributed to the field of CCM, most specifically to its clinical diagnosis. A greater understanding of the genetics involved in CCM will facilitate and permit better management care for patients. Furthermore, the possibility of identification of a gene with a major effect for IA will give us more insight into which pathways are involved in IA formation.

No description available.

According to the literature, MRI has been applied to characterize the atherosclerosis in coronary and extracranial internal carotid artery. The cross-sections of MCA were scanned by Magnetic Resonance Imaging (MRI) to assess the accuracy of MRI in identifying MCA stenosis with histopathology as a golden standard, which was performed in the same post-mortem brains as in the second part. The sensitivity and specificity of MRI in detecting more than 30% MCA stenosis were 38.6% and 92.2%, with a positive predictive value of 87.2% and negative predictive value of 52.2%, and the corresponding values of MRI in identifying more than 50% MCA stenosis were 57.1%, 90.8%, 50% and 83.0%, respectively. Stenotic lesions >30% and >50% identified by MRI were found to be associated with infarctions in corresponding MCA territory. / After verification of potential relationship between ischemic stroke and intracranial artery calcification, the incidence of intracranial artery calcification was assessed in the ischemic stroke. One hundred and seventy-five ischemic stroke patients and 182 controls were enrolled. There was a higher prevalence of intracranial artery calcification in ischemic stroke patients than in controls. Hypertension, diabetes, smoking, intracranial artery calcification, hyperlipidemia, and atrial fibrillation were found to be independently associated with ischemic stroke. / Atherosclerotic stenosis is a heterogeneous disorder. The studies performed in extracranial carotid artery and coronary artery showed that the genes associated with lipoprotein metabolism may be associated with atherosclerosis. Thus, we speculated that the genes concerned with lipid metabolism may also be risk factors for MCA atherosclerotic stenosis. In the part of genetic analysis, clinical parameters and the genotypes of polymorphisms in the apolipoprotein E (ApoE), lipoprotein lipase (LPL), and paraoxonase (PON1) genes were compared in patients with and without MCA stenosis. Two hundred and ninety-four ischemic stroke patients were recruited, 136 cases with and 158 without MCA stenosis. Systolic blood pressure (SBP), rather than ApoE, LPL, and PON1 polymorphism was found to be a risk factor of MCA stenosis. / Calcification of intracranial artery, as a common complication of atherosclerosis, was investigated by multi-detector-row computed tomography (MDCT). By this advanced technique, the prevalence and location of calcification in intracranial arteries were determined, and its potential risk factors were also investigated. Four hundred and ninety patients were recruited. The incidence of intracranial artery calcification was 69.4%. The highest prevalence of intracranial artery calcification was seen in internal carotid artery (60%), followed by vertebral artery (20%), middle cerebral artery (5%) and basilar artery (5%). Age, a history of ischemic stroke, and white blood cell count were shown to be independently associated with intracranial artery calcification. / In the present study, genetic, pathological, imaging characterizations and prognosis of MCA stenosis were investigated. The effect of candidate genes has not been confirmed in the present study, but SBP and hypertension appears to contribute a lot to the occurrence of MCA stenosis among Chinese populations. As for the pathology of MCA atherosclerotic plaques, luminal stenosis and also the morphology of atherosclerotic plaque seem to play a cooperative role in leading to ischemic stroke. Imaging studies demonstrated the agreement between ex vivo MRI and histopathology in identifying MCA stenosis, and the correlation between the MCA stenosis identified by MRI and ischemic events. Calcification of intracranial artery, as a common complication of atherosclerosis, may be associated with age, history of ischemic stroke. High incidence of ischemic stroke has been demonstrated in Chinese type 2 diabetes patients. The presence of asymptomatic MCA stenosis plays an important role in the occurrence of ischemic stroke. / Lastly, using a cohort-study, we aimed to investigate stroke incidence of asymptomatic MCA stenosis and its risk factors in Chinese type II diabetic population. Transcranial Doppler was performed to define MCA stenosis. Incident strokes between 1996 and 2006 were ascertained by the database of Clinical Management System of the Hong Kong Hospital Authority. Anthropometric parameters (waist circumference and body mass index), blood pressure, and baseline plasma biochemical profile (lipid and glucose) were recorded to find the risk factors of ischemic stroke in asymptomatic MCA stenosis patients. Totally, 2,197 type II diabetic patients without symptoms of cerebrovascular disease were recruited. The evidence of MCA stenosis was identified in 272 subjects (12.4%), including 146 (53.7%) subjects with single-vessel involvement. Ischemic stroke occurred in one hundred and eighty-four (8.4%, 184/2197) patients. History of ischemic heart disease, MCA stenosis, the presence of retinopathy, lipid total cholesterol and age were independently associated with ischemic stroke. / Secondly, the pathological features of MCA stenosis and their relationship with cerebral infarcts were investigated in a series of post-mortem adults aged 45 years or above. The morphological features of the MCA atherosclerotic plaques were described in detail. The results demonstrated that the degree of luminal stenosis, the percentage of the plaques containing more than 40% lipid area, the values of cap-lipid, cap-lipid-stenosis, and the prevalence of intraplaque hemorrhage, neovasculature and thrombus were higher in the group of plaques associated with infarction. And the mean index of both CD45RO and CD68 were higher in the group of plaques associated with infarction. Binary logistic regression showed that stenosis, lipid area and presence of neovasculature were independent risk factors of MCA infarcts. / Stroke is one of the leading causes of death, disability, and dementia throughout the world. The stenosis of the intracranial large artery, especially the middle cerebral artery (MCA), is common in Chinese, Hispanic, and African populations. But MCA stenosis has been understudied due to its infrequency in the white population and its relative inaccessibility and invasiveness involved in its investigations. The purpose of the study was to investigate the genetic, pathological, imaging characteristics and prognosis of MCA atherosclerotic stenosis in Chinese population. / Chen Xiang-yan. / "September 2006." / Adviser: MH Ng. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1460. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 193-212). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Made available in DSpace on 2016-01-26T12:51:25Z (GMT). No. of bitstreams: 1 marcosluiztostesdossantos_dissert.pdf: 2066322 bytes, checksum: 9abf4b93ab3ce79b49c60b4edd0f3b0c (MD5) Previous issue date: 2007-11-06 / Brain arteriovenous malformations (BAVM) are morphological and neurovascular abnormalities characterized by direct communication between arteries and veins, without interposition of capillary bed, therefore without resistance to blood flow. OBJECTIVE: The purpose of this research was to characterize morphologically brain arteriovenous malformations aiming correlation with clinical presentation. CASUISTIC AND METHOD: A total of 170 patients with brain AVM, 78(46%) males and 92(54%) females, were studied from January 2001 to January 2007 at the Vascular and Endovascular Neurosurgery Unit of the Hospital de Base of São José do Rio Preto, SP. Univariate and multivariate analyses were conducted to test the associations among demographic (sex, age), clinical (hemorrhage, seizure, focal neurological deficit, and headache), and morphological features (anatomical localization; superficial, deep, infratentorial or supratentorial location; nidus size; number of feeding arteries, compartments, and draining veins; type of venous drainage; presence of stenosis, venous ectasias, and arterial aneurysms; Spetzler-Martin classification). RESULTS: The main clinical presentations at the moment of diagnosis included hemorrhage in 89 (52%) patients, headache in 79 (46%), focal neurological deficit in 54 (32%), and seizure in 52 (31%). According to the Spetzler-Martin classification, grade I was found in 15 (9%) patients, grade II in 49 (28%), grade III in 55 (33%), grade IV in 41 (24%), and grade V in 10 (6%) patients. There was a statistically significant association among hemorrhage and small nidus size (p = 0.002), single feeding artery (p = 0.007), single draining vein (p = 0.003), and single compartment (p = 0.040). Seizure was positively correlated with medium (3-6 cm) and large nidus size (>6cm), and negatively with small nidus size (<3cm) (p = 0.021). CONCLUSIONS: Brain AVM with small nidus size, Spetzler-Martin grade I, single feeding artery and draining vein are associated with hemorrhage. Spetzler-Martin grade V was negatively associated with hemorrhage. In the braim AVM there is no association between aneurysm and hemorrhage. On the other hand, seizure show positive correlation with large nidus size and negative with small nidus size. / Malformações arteriovenosas (MAV) encefálicas são anomalias morfológicas neurovasculares caracterizadas por comunicação direta entre artérias e veias, sem interposição do leito capilar, portanto sem resistência ao fluxo sangüíneo. OBJETIVO: O objetivo desta pesquisa foi caracterizar morfologicamente MAV encefálicas, visando correlação com apresentação clínica. CASUÍSTICA E MÉTODO: Foram estudados 170 pacientes portadores de MAV encefálicas, sendo 78 (46%) do sexo feminino e 92 (54%) do masculino, no período de janeiro de 2001 a janeiro de 2007, atendidos na unidade de Neurocirurgia Vascular e Endovascular do Hospital de Base de São Jose do Rio Preto, SP. Análises univariada e multivariada foram efetuadas para testar associações entre características demográficas (sexo, idade), clínicas (hemorragia, convulsão, déficit focal, cefaléia) e morfológicas (localização anatômica; posição superficial, profunda, infratentorial ou supratentorial; tamanho do nidus; número de aferências, compartimentos e eferências; padrão de drenagem venosa; presença de estenose, ectasias venosas e aneurismas arteriais; classificação de Spetzler-Martin). RESULTADOS: As principais formas de apresentação clínica no momento do diagnóstico incluíram hemorragia em 89 (52%) pacientes, cefaléia em 79 (46%), déficit focal em 54 (32%) e convulsão em 52 (31%). De acordo com a classificação de Spetzler & Martin, 15 (9%) pacientes tinham MAV grau I, 49 (28%) grau II, 55 (33%) grau III, 41 (24%) grau IV, e 10 (6%) grau V. Houve associação estatisticamente significativa entre hemorragia e tamanho pequeno do nidus (p = 0,002), aferência única (p = 0,007), eferência única (p = 0,003) e compartimento único (p = 0,040). Convulsão foi correlacionada positivamente com nidus de tamanho médio (3-6 cm) e grande (>6cm) e negativamente com tamanho pequeno (<3cm) (p = 0,021). CONCLUSÕES: MAV encefálicas com nidus de tamanho pequeno, grau I, aferência e eferência únicas estão associados à hemorragia. MAV encefálicas grau V estão associadas negativamente à hemorragia. Na MAV encefálica observa-se ausência de associação entre aneurisma e hemorragia. Por outro lado, convulsão mostra correlação positiva com nidus de tamanho grande e negativa com nidus de tamanho pequeno.