Dissertations / Theses on the topic 'Microbleeds'

Advances in MR technology have improved the potential for visualization of small lesions in brain images. This has resulted in the opportunity to detect cerebral microbleeds (CMBs), small hemorrhages in the brain that are known to be associated with risk of ischemic stroke and intracerebral bleeding. Currently, no computerized method is available for fully- or semi-automated detection of CMBs. In this paper, we propose a CAD system for the detection of CMBs to speed up visual analysis in population-based studies. Our method consists of three steps: (i) skull-stripping (ii) initial candidate selection (iii) reduction of false-positives using a two layer classi cation and (iv) determining the anatomical location of CMBs. The training and test sets consist of 156 subjects (448 CMBs) and 81 subjects (183 CMBs), respectively. The geometrical, intensity-based and local image descriptor features were used in the classi cation steps. The training and test sets consist of 156 subjects (448 CMBs) and 81 subjects (183 CMBs), respectively. The sensitivity for CMB detection was 90% with, on average, 4 false-positives per subject.

Cerebral Microbleeds (CMB) are small chronic brain haemorrhages, known as paramagnetic blood products, and likely caused by structural abnormalities of the small vessels. The concept of CMB is primarily a radiological construct describing small MRI signal voids. They are often present with cerebrovascular disease, dementia, Alzheimer’s disease, and normal aging people. Substantial progress has been made in recent years, in developing MRI methodologies showing CMB, such as susceptibility-weighted imaging (SWI) which is sensitive to differences in tissue magnetic susceptibility. In SWI, residual paramagnetic blood products appear with a lower intensity and are therefore suitable for detecting CMB, showing as hypointense amorphous small semi-spherical blobs. However, on visual inspection of SWI scans, CMB appearance can easily be confounded with small blood vessels cross-sections. The detection of CMB from MRI is clinically important and has generated increasing interest as an imaging marker of vessel diseases and cognitive dysfunctions. Being subjective, time-consuming, and high missing rates are some critical challenges of human rating. Computer-aided algorithms are being proposed to detect CMB for different MRI modalities with the aim of increasing sensitivity and reducing the number of false positives. However, the lack of ground truth leads to the imbalanced data problem and overfitting. To cope with the lack of dataset, traditional data augmentation methods, undersampling, cost-sensitive matrices are employed to mitigate the imbalanced data during classifier training. There are some problems behind with these applied solutions. Undersampling could omit some informative negative samples, traditional data augmentation methods are highly dependent on the diversity and availability of the ground truth, and the cost-sensitive matrix is not a general solution. Data privacy is a critical issue in medical research and it is essential to highlight that research and public health activities need to be carried out in ways that protect individuals’ privacy. Therefore, the demand to generate synthetic data is increasing. This thesis proposes a synthetic CMB generation model independent of the ground truth availability, and with the capability of being adaptable to new MRI modalities. The second aim is to improve CMB classification by using synthetic CMB in the classifier to achieve high sensitivity with low false positives. To propose our synthetic CMB generation model, we exploited our limited ground truth from SWI MRI images. Some features such as location, intensity, size and shape were extracted to get intuition from real CMB. The Gaussian mixture model was applied to distinguish background and outliers and extract a binary CMB mask to compute volume. To have information about the Microbleeds’ location, we defined our tissue mask including gray matter, white matter, ventricle, and cerebrospinal fluid to compute distance distribution and CMB proportion for each region. For shape, and intensity, the average of all real CMB and minimum intensity values was computed. After analysing the real CMB’s characteristics, we proposed our analytical model to generate synthetic CMB. The model is based on the hypothesis that the rCMB are Gaussian-like structures, elongated in z direction, and spreading all over the brain with low-intensity value. There are some benefits to using an analytical model. The model can cover the diversity of the CMB in location and shape by adding random parameters. In addition, any classifier could be trained only on the synthetic data and tested on the real limited lesions. Extensive validation and testing experiments become possible by using synthetic data. The dataset with 37,000 synthetic lesions is publicly available for the research community. To evaluate the generalization of our proposed analytical model, we applied the model to QSM images for the same patients. The main contribution is that our proposed analytical model can be applied to another MRI modality without extensive parameter changes when CMB appears with different contracts. CMB classification shows improvements over traditional data augmentation from QSM images. The conditional generative adversarial network is another model that we exploited for the synthetic CMB generation that forms the main contribution in this thesis. Our proposed model is independent of any MRI imaging parameters. It can learn the effect of the CMB on the surrounding tissue. Synthetic Microbleeds could be generated with shape diversity related to any desire locations in the brain, and the model can be applied to a new dataset and improve the CMB classification for an unseen dataset with different MRI parameters, and disease categories with limited ground truth.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Eng & Built Env<br>Science, Environment, Engineering and Technology<br>Full Text

Les micro-saignements cérébraux (MSC) sont des dépôts d’hémosidérine particulièrement visibles sur des séquences IRM sensibles à la susceptibilité magnétique, comme par exemple la séquence en écho de gradient pondérée (GRE) en T2*. Néanmoins, leur détection in-vivo à partir de l’image d'amplitude GRE T2* obtenue en routine clinique est peu exacte et très sensible aux paramètres d’acquisition. Une détection automatique des MSC permettrait d’augmenter la portée et la pertinence de cette séquence, mais il est avant tout nécessaire de mieux caractériser les MSC pour augmenter la spécificité de détection. Cette thèse présente une nouvelle méthode pour extraire l’information d’intérêt (la carte champ interne) à partir d’images de phase obtenues avec les mêmes acquisitions cliniques GRE T2*. En effet, l’image de phase T2* contient directement une information sur la susceptibilité et pourrait donc améliorer la détection des MSC. Cette méthode a été évaluée avec succès sur des données multicentriques de qualité compatible avec la routine clinique pour des sujets avec un nombre très variable de MSC et a permis de différencier les MSC des micro-calcifications. Une étude de validation a également été menée pour évaluer l’utilité clinique de la carte de champ interne pour la détection par un expert, par rapport à d’autres types d’images et reconstructions utilisées en clinique. Elle a montré une amélioration de la spécificité. La thèse comprend également une preuve de concept d’une méthode d’identification automatique utilisant l’information provenant de plusieurs types d’image et de reconstruction afin d’augmenter la spécificité de l’identification. L’évaluation est menée sur les sujets précédemment décrits. Cette preuve de concept est basée sur un algorithme d’apprentissage supervisé ; cela consiste à combiner les informations issues des différents types d’image à partir desquels des descripteurs d’intensités et de forme ont été extraits pour créer un modèle de prédiction permettant discriminer les MSC<br>CMBs, small hypo-intense foci with a maximum diameter of 10 millimeters, were first thought clinically silent. They are now considered as an imaging marker of cerebral small vessel diseases and their clinical involvement is increasingly recognized; they may be associated with an increased risk of hemorrhagic stroke, ischemia and dementia such as Alzheimer's disease. However, their relation with pathology and its causality remains largely to be understood, partly because of their tricky characterization in-vivo. Large scale studies or meta-analyses are made difficult because their identification varies with MRI sequence parameters and suffers from reproducibility issues and is time-consuming. Automatic identification methods have been proposed to address these issues but they all require manual post processing selection steps, because of a very high number of false positives. This suggests that a better characterization of CMBs may be the key to improve their detection, as it would allow better identifying them from misleading structures and lesions.This PhD focused on achieving a better characterization of CMBs to better detect them with an automatic method. It covers multiple aspects to improve CMBs identification. First, MR phase image was taken into account in addition to the standard MR magnitude image, because of its sensitivity to CMBs. A new MR phase image processing technique was thus developed to obtain the magnetic field of interest free of contamination from background sources in datasets equivalent to clinical routine. A comparison study was carried-out to evaluate the outcome of this tool for CMBs detection in a standardized dataset in a clinical environment. A proof-of-concept is given to illustrate the advantages of new features for automatically identifying CMBs

Introduction: A portfolio of studies is presented aimed at understanding the clinical and pathophysiological significance of cerebral microbleeds (CMBs) in stroke patients. CMBs are the radiological marker of microscopic haemosiderin deposits on iron-sensitiveMRI sequences (mainly gradient-recalled echo [GRE] T2* MRI). They are common in patients with cerebrovascular disease and are hypothesised to be a biomarker for brain small vessel diseases, including hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Important questions relating to CMBs include their use as a prognostic marker for antithrombotic-related intracerebral haemorrhage (ICH) and cognitive impairment. Our aims were to address the pathophysiological and clinical relevance of CMBs using longitudinal, case-control and cross-sectional studies. Methods: Patients were ascertained from prospective databases of admissions to the stroke service at the National Hospital for Neurology and Neurosurgery and at University College London Hospital’s (UCLH) NHS Trust. Magnetic resonance imaging data was collected and analysed for markers of small vessel disease including CMBs. Clinical and radiological associations of CMBs were determined using appropriate statistical tests. Objectives: First, ways of improving microbleed detection and reporting were explored through the development of a visual rating scale (theMicrobleed Anatomical Rating Scale, MARS) aimed at reliably rating CMBs. Second, the prognostic relevance of CMBs was investigated for antiplatelet-related ICH in a case-comparison study. Third, the detection of new CMBs over time and the factors that influence this were explored. Fourth, the impact of CMBs on cognitive impairment was studied in a cross-sectional study. Finally, the association between CMBs and acute silent ischaemia on diffusion-weighted MRI was investigated via a multi-centre cross-sectional MRI study of patients with ICH. Main findings: 1. MARS is a reliable scale with good intra- and inter-rater agreement for rating CMBs presence and number in any brain location. 2. Lobar CMBs, especially if numerous, are a risk factor for antiplatelet-related ICH independent of the extent of white matter changes. 3. CMBs accumulate over time in stroke patients, and the risk is related to baseline systolic blood pressure. 4. Lobar CMBs are an independent predictor of frontal executive impairment; this suggests that CAA is a potential underlying contributor to cognitive impairment. 5. Silent acute infarcts are frequent in patients within 3 months of ICH, especially in those with probable CAA, and are associated with markers of small vessel disease severity, including CMBs. Conclusion: These studies provide new information on detection, clinical impact and associations of CMBs in stroke patients. They suggest that CMBs have useful roles in understanding pathophysiology, diagnosis and prognosis in patients with small vessel diseases. Further studies are required to determine the direct therapeutic consequences of CMBs, but the present work suggests several promising areas for future research.

La maladie d'Alzheimer (MA) est un processus multifactoriel. La dysfonction vasculaire pourrait être impliquée dans sa progression. Les microhémorragies cérébrales (MH) sont fréquentes chez les patients atteints de MA, et pourraient jouer un rôle clé dans le lien qui relie la dysfonction vasculaire à la MA. Le sexe pourrait également impacter sur la sévérité des lésions. Les statines ont été proposées en prévention de maladies neurodégénératives dont la MA. Leur intérêt est encore débattu mais ces molécules ont une action pléiotrope. Ce travail a pour objectif d'étudier l'impact des lésions microhémorragiques sur le déclin cognitif dans la MA, le rôle du sexe et la modulation pharmacologique par Atorvastatine, dans une perspective translationnelle,i.e. en considérant à la fois l'aspect expérimental chez l'animal et l'aspect clinique. Pour la partie expérimentale, nous avons étudié à partir d'un modèle original de MH chez les souris femelles saines et pathologiques. La MHC est créée par injection stéréotaxique de Collagénase (0,8|uUI/|iL). L'atorvastatine est administrée dans l'alimentation quotidienne des rongeurs(5mg/Kg/J). Le suivi était multimodal à trois temps différents : six semaines, six mois et douze mois après la chirurgie. Au plan clinique, nous avons étudié une base de données de patients atteints de la MA, suivis de façon standardisée. Notre travail a mis en évidence, dans une approche translationnelle, un impact cognitif et non cognitif des MHs, en présence ou non d'une maladie d'Alzheimer chez le sexe féminin. Nos résultats tendent à confirmer l'intérêt de l'atorvastatine dans la neuroprotection, grâce à ses effets pléiotropes. D'une manière générale,notre travail souligne, une fois de plus, l'intérêt d'une prise en charge personnalisée, et précoce de la MA<br>The physiopathology of Alzheimer disease (AD) is complex. Associated factors, in particular at the vascular level with damaged small blood vessels, might be involved. Cerebral microbleeds(CMB) in particular, could be one of the key contributing factor in AD. The cumulative evidence suggested a sex-specific patterns of disease. Furthermore, statins might be interesting by pleitropic effects. The objectives of this study was to evaluate the interaction between vascular and neurodegenerative lesions in Alzheimer, the influence of sex, and the pharmacological modulation by atorvastatin. This experimental model is designed in a multimodal approach to ensure its scientific relevance and to fit with clinical research. The third objective is indeed to confront theresulting experimental data to the clinical data of cohorts of Alzheimer patients. With an original model of CMB in female mice, we folio wed-up them from 1.5 months to 12 months postsurgery.For the clinical part, we studied patients with AD from a database of a tertiary memory center, with standardized framework. In a translational way, we observed a cognitive and a non cognitiveimpact of CMBs, differently in wild-type mice and in diseased mice. Different outcome was noticed for young female mice. And Atorvastatine offered a mild neuroprotection particularly in presymptomatic stage. Finally, the mechanism implied will be studied, in particular the inflammatory pathway, and will help to propose targeted pharmacological modulation in order to prevent or limit the impact of CMB on AD, by offering a personalized approach

L’augmentation de la prévalence des hémorragies cérébrales (HC) sous traitement antithrombotique constitue un problème de Santé Publique à cause du mauvais pronostic vital et fonctionnel et du risque compétitif de récidive hémorragique ou ischémique chez les survivants, qui pose le problème d’une prévention secondaire adaptée._x000D_L’objectif de la thèse était d’étudier l’impact des traitements antithrombotiques sur le pronostic des HC. Le terme d’HC, entendu au sens large, regroupe les HC spontanées et les microhémorragies cérébrales.La première partie avait comme objectif de comparer les caractéristiques des HC survenant avec ou sans traitement par antagonistes de la vitamine K (AVK), stratifiant l’analyse selon la localisation de l’HC. L’analyse a porté sur 545 patients de la cohorte Lilloise (PITCH), parmi lesquels 83 (15%) étaient sous AVK. La prise d’un traitement par AVK n’influençait pas la localisation de l’HC, mais était prédictive d’HC plus volumineuses (25 ml vs 12 ; p=0.002) chez les victimes d’HC non lobaire, alors que aucune différence existait en cas d’HC lobaire (26 ml vs 30; p=0.507). Ces résultats suggèrent que l’impact des AVK diffère en fonction de la localisation de l’HC et de la vasculopathie sous-jacente.La deuxième partie avait comme objectif d’analyser l’impact du traitement antithrombotique sur l’apparition de nouvelles microhémorragies cérébrales stratifiant l’analyse selon la localisation de l’HC. L’étude a porté sur 168 survivants à 6 mois d’une HC (cohorte PITCH) ayant bénéficié d’une IRM cérébrale 1.5T lors de l’HC et durant le suivi. Lors de l’HC, 89 (53%) patients présentaient des microhémorragies, et 80 (48%) ont développé des microhémorragies durant le suivi. La présence sur la première IRM de microhémorragies (aOR 2,3; IC 95%1,2-4,3), leur position mixte, lobaire et profonde (aOR 3.7; IC95% 1,7-8,3), et la présence de séquelles de macrohémorragies (aOR 6,8; IC95% 2,8-16,7), étaient associées à l’apparition de microhémorragies. Chez les patients avec HC non lobaire, l’apparition de microhémorragies était associée à l’utilisation d’un traitement antithrombotique durant le suivi (aOR 2,9 ; IC95% 1,1-7,3) et avec l’apparition de lacunes (aOR: 2,9; 95%CI 1,0-7,8). Chez les patients avec HC lobaire, l’apparition de microhémorragies était associée à l’apparition de macrohémorragie (aOR 9.8 ; IC95% 1,1-88,8). Ces résultats suggèrent que l’impact des traitements antithrombotiques diffère en fonction de la vasculopathie sous-jacente.La troisième partie avait comme objectif de : (i) comparer les proportions de survivants d’une HC ayant une indication formelle au traitement antithrombotique chez lesquels ce traitement était repris à la sorite ; (ii) identifier les caractéristiques associées à la reprise du traitement antithrombotique, au sein de 5 cohortes européennes (Lille, n=542; Utrecht, n=389 ; Amsterdam, n= 403 ; Londres, n=667 ; Lothian, n=137). Un traitement antithrombotique était recommencé chez 96 (20%) des 469 survivants ayant une indication formelle, mais en proportions différentes dans les 5 cohortes (Lille 18%, Utrecht 45%, Amsterdam 30% ; Londres 11% ; Lothian 15%; p&lt;0.001). Nous n’avons retrouvé aucun autre facteur prédictif de reprise du traitement antithrombotique en dehors de la cohorte d’origine. Ces résultats montrent que la décision de reprise du traitement antithrombotique ne repose pas sur des critères reproductibles, et soulignent la nécessité de réaliser des essais randomisés.La quatrième partie, actuellement en cours, prévoit d’évaluer chez ces mêmes patients (survivants d’une HC ayant une indication formelle au traitement antithrombotique) le risque de récidive hémorragique ou ischémique en fonction de la reprise ou de l’arrêt du traitement antithrombotique. Il s’agit d’une étude observationnelle portant sur 274 patients de 4 cohortes Européennes, avec un suivi d’environ 2.5 ans. L’analyse statistique est en cours<br>The proportion of patients who are taking antithrombotic drugs at the time they suffer a spontaneous intracerebral hemorrhage (ICH) is increasing over time, and this is a major issue in public health because of the poor prognosis of patients. Also, the decision to restart or not antithrombotic drugs in survivors is still a clinical dilemma. _x000D_The aim of this work was to evaluate the impact of antithrombotic drugs on ICH prognosis. The term ICH regroups (i) spontaneous ICH and (ii) cerebral microbleeds (CMBs).As a first step, we compared baseline characteristics of 545 consecutive patients with ICH included in the PITCH cohort (Lille, France), receiving or not Vitamin K Antagonists (VKAs) at the time of ICH, stratifying the analysis according to the ICH location (lobar vs non lobar). VKAs-ICH accounted for 83 patients (15%). The use of VKAs did not influence ICH location, but influenced ICH volume: in non lobar ICH, VKAs use was associated with larger ICH volumes (25 ml versus 12 ml, p=0.002). In lobar ICH, no difference was observed (26ml versus 30ml; p=0.507). The different impact of VKAs on ICH volumes according to location suggests a different susceptibility of the underlying vasculopathies to VKAs.As a second step, we aimed to evaluate the impact of antithrombotic drugs on the incidence of CMBs in 168 ICH survivors from the PITCH cohort who underwent 1.5T Magnetic resonance imaging (MRI) at ICH onset and during follow-up, stratifying the analysis according to the index ICH location. At the time of ICH, 89 (53%) patients had CMBs at ICH onset, and 80 (48%) showed new CMBs during follow-up. Predictors of incident CMBs were the presence on the first MRI of: at least 1 CMB (aOR 2.3; 95% CI: 1.2-4.3), old macro-hemorrhage (aOR 6.8; 95%CI 2.8-16.7), and CMBs in mixed location (aOR 3.7; 95%CI 1.7-8.3). In non lobar ICH, incident CMBs were associated with incident lacunes (aOR: 2.9; 95%CI 1.0-7.8) and with the use of antiplatelet agents (aOR 2.9; 95%CI 1.1-7.3). In lobar ICH, incident CMBs were associated with incident macro-hemorrhage (aOR 9.8; 95%CI 1.1-88.8). These results suggest that the impact of antithrombotic drugs differs according to the index ICH location, and therefore according to the underlying vasculpathy.The third step consisted in comparing the characteristics and proportions of patients taking antithrombotic drugs at ICH discharge in five European cohorts (Lille, France, n=542; Utrecht, The Netherlands, n=389; Amsterdam, The Netherlands, n=403; multicenter UK cohort, n=667; Lothian, Scotland, n=137). We then identified characteristics associated with restarting. Antithrombotic drugs were restarted in 96 (20%) of the 469 survivors who had an indication for antithrombotic drugs (secondary prevention or atrial fibrillation), but in different proportions according to the cohort of origin (Lille 18%, Utrecht 45%, Amsterdam 30%, CROMIS-2 ICH 11%, Lothian 15%; p&lt;0.001). We did not find other consistent associations with restarting antithrombotic drugs. The variation in clinical practice in restarting antithrombotic drugs after ICH supports the need for randomized controlled trials.In the fourth step, we aim to analyse the risk of ICH recurrences or ischemic events in the same population of patients (ICH survivors who suffered from ICH while on antithrombotic drugs because of secondary prevention or atrial fibrillation) according to the antithrombotic drug status during follow-up. We included 274 patients from 4 European cohorts, with a median follow-up of 2.5 years. Statistical analysis is ongoing

La réparation valvulaire aortique percutanée a connu d’immense progrès depuis unevingtaine d’années permettant au patient atteint de rétrécissement aortique (RA) serré debénéficier d’un traitement curatif, le plus souvent avec une approche minimaliste sous anesthésielocale associée à une diminution des complications procédurales. Cependant la prise en charge decertaines situations cliniques d’urgence ou de certains patients à haut risque opératoire est encoremal définie et nécessite une évaluation précise des complications ischémiques et hémorragiquesde la procédure percutanée.Dans la première partie de la thèse nous avons confirmé que certaines situations cliniquescomplexes urgentes telles qu’un état de choc cardiogénique secondaire à un RA serré, ou lanécessité d’une chirurgie extracardiaque urgente constituent encore une zone grise où letraitement optimal du RA n'est pas clair et nécessite de plus amples investigations. Dans le choccardiogénique ou la chirurgie extracardiaque urgente, le risque de complications hémorragiqueset surtout ischémiques et la mortalité à court terme restent très élevés. En cas de choccardiogénique, les complications sont principalement reliées au timing de la valvuloplastieaortique (BAV). En cas de chirurgie extracardiaque urgente, la BAV systématique n’améliore pasle pronostic par rapport au traitement médical.Dans la deuxième partie de la thèse, chez des patients à risque intermédiaire ou élevécontre indiqué à l’accès transfémoral pour un TAVI, nous avons comparé les deux voiesalternatives extrathoraciques les plus utilisées : axillaire et carotidienne. Celles ci font jeu égal enterme de complications ischémiques et de mortalité mais l’accès carotidien semble avoir plus decomplications hémorragiques en particulier locales.La troisième et dernière partie de la thèse nous a permis d’apprécier l’incidenceimportante de microbleeds au cours de la procédure TAVI. Leur apparition semble être reliéeavec la durée de la procédure et l’absence de correction du déficit en facteur Willebrand acquislors du RA ; ces lésions n’ont pas de retentissement sur l’évolution neurologique à court terme(6mois). Des études sont en cours pour mieux préciser le lien entre risque hémorragique cérébral,anomalie du facteur vWF et dispositif cardiaque valvulaire ou d’assistance<br>Ischemic and haemorrhagic complications during percutaneous aortic valve interventionsPercutaneous aortic valve repair including balloon aortic valvuloplasty (BAV) and TAVI has experienced significant improvements over the past twenty years, allowing patients with severe aortic stenosis (SAS) to benefit from a curative treatment, mostly with a minimalist approach under local anesthesia associated with a drastic reduction of procedural complications.However, the management of specific clinical emergency situations or of high-risk patients is still poorly explored and requires an accurate assessment of the ischemic and hemorrhagic complications of percutaneous procedures.In the first part of this thesis, we confirmed that some urgent complex clinical situations such as cardiogenic shock secondary to SAS, or the need for urgent extracardiac surgery in SAS patients still constitute a grey zone where the optimal treatment is unclear and requires further investigations. During cardiogenic shock or urgent extracardiac surgery, the risk of hemorrhagic and especially ischemic complications and short-term mortality remain very high. During cardiogenic shock, complications are mainly related to the timing of the BAV. When urgent extracardiac surgery is required, routine BAV does not improve the prognosis of SAS patients compared to medical treatment.In the second part of this thesis, we compared the axillary and carotid access in intermediate or high-risk patients contraindicated to transfemoral route for TAVI. These accesses have similar rates of ischemic complications and mortality, but carotid artery has more local hemorrhagic complications.The third and final part of this thesis analyse the significant incidence of microbleeds during the TAVI procedure. Their appearance seems to be related to the duration of the procedure and the lack of correction of the von Willebrand factor deficiency acquired during SAS; these lesions have no impact on the neurological evolution in the short term.Studies are underway to better define the link between the risk of cerebral hemorrhage, the vWF factor and cardiac valvular or circulatory assist device

En imagerie par résonance magnétique (IRM), les MHC apparaissent comme des petites lésions arrondies et en hyposignal correspondant à des dépôts d’hémosidérine. La prévalence des MHC dans la population générale est d’environ 15,3%. Considérées comme des marqueurs des pathologies cérébrovasculaires, les MHC sont plus fréquentes chez les personnes atteintes de troubles cognitifs ou de démence avec une prévalence de 23% chez les patients atteints de la maladie d’Alzheimer (MA). Plusieurs études cliniques montrent un effet des MHC sur les fonctions cognitives dans la population générale. Elles pourraient jouer un rôle important dans la physiopathologie de la MA en créant un lien entre les hypothèses amyloïdes et vasculaires mais leur impact cognitif dans ce contexte reste encore indéterminé.Un nouveau modèle murin de microhémorragie corticale (MHC) a été développé afin d’étudier l’impact fonctionnel d’une lésion corticale avec une approche multimodale : i) sur des souris sauvages (WT) sans aucune pathologie sous-jacente, ii) sur les souris de la lignée J20 exprimant le précurseur de la protéine amyloïde humaine muté (APP). L’effet d’une modulation pharmacologique par atorvastatine a également été étudié.La MHC a été induite par injection stéréotaxique de collagénase (0,8 μUI/μL) chez des souris WT et APP âgées de 10 semaines. Une IRM a été réalisée à 24 heures (séquence T2*) pour visualiser le saignement. Les souris ont été réparties en groupes sham, MHC et MHC avec traitement. L’atorvastatine a été administrée via l’alimentation quotidienne à la posologie de 5mg/kg/j et initiée après la chirurgie. Le suivi était constitué d’une évaluation neurocomportementale (activité locomotrice spontanée, niveau d’anxiété, mémoire de travail, mémoire de référence spatiale et mémoire visuospatiale), et des mesures paracliniques (IRM 7 Tesla, tomographie à émission de positons, immunohistochimie) réalisées à différents temps allant de 1,5 à 12 mois post-chirurgie.Une cohorte de souris WT et APP a été suivie de façon longitudinale sur 12 mois post-chirurgie. Une première évaluation des souris WT à 6 semaines post-chirurgie a démontré un impact de la MHC sur l’anxiété et les mémoires de référence spatiale et visuospatiale. L’amélioration des performances chez les souris traitées a montré la sensibilité du modèle à une modulation pharmacologique par statine. Aux temps d’évaluation à 1,5, 3, 6, 9 et 12 mois, chez les souris WT, le groupe avec MHC a montré un niveau d’anxiété diminué et une altération de la mémoire de référence spatiale à 1,5 mois retrouvée à 9 et 12 mois. Cette étude n’a pas permis de conclure à un effet précipitant ou aggravant de la MHC chez la souris APP. Le traitement par atorvastatine a montré un effet positif sur la cognition chez les souris WT. A 12 mois, une diminution des volumes hippocampiques ipsilatéraux a été observée chez tous les groupes sans exception. Aucun effet de la MHC ou du traitement n’a été constaté sur le métabolisme cérébral.En clinique, une hypothèse propose que les MHC pourraient, par leur présence, entrainer des troubles cognitifs. L’autre les présente comme le reflet des atteintes cérébrovasculaires, elles-mêmes responsables des altérations cognitives. Cette étude a permis de démontrer qu’une MHC isolée peut altérer les fonctions cognitives chez les souris WT, en dehors de toute pathologie sous-jacente. Chez les souris APP, le poids des lésions neurodégénératives ne permet pas de mettre en évidence l’effet de la MHC. L’atorvastatine semble avoir un effet neuroprotecteur<br>In magnetic resonance imaging (MRI), cerebral microbleeds (CMB) appear as small, oval hypointense lesions corresponding to focal hemosiderin depositions. CMB prevalence in the general population is about 15,3%. Considered as biomarkers of small vessel diseases, CMBs are more frequent in people with cognitive impairments or dementia with a prevalence of 23% in A.lzheimer disease (AD). Several population-based studies show an effect of CMBs on cognitive functions. They could have a key role in AD pathophysiology creating a link between amyloid and vascular hypothesis. However, their cognitive impact in AD remains unclear. A new murine model of cortical microhemorrhage (CMH) has been developed in order to study with a multimodal approach, the functional impact of the cortical lesion: i) in Wild type (WT) mice without any underlying pathology, ii) in transgenic J20 mice expressing the human mutated amyloid protein precursor (APP). The effect of a pharmacological modulation by atorvastatin was also studied in this model._x000D_10 weeks-old male mice, WT and APP were operated by stereotaxic injection of collagenase 0.8 µUI/µL to induce the CMH. 24 hours after surgery, mice underwent MRI acquisition (T2* sequence) to visualize the bleeding. Mice were divided into sham, CMH and CMH treated by atorvastatin groups. Atorvastatin was administered by mixing a tablet into the mice’s standard chow at a dose of 5mg/kg/day and initiated after surgery. Follow-up included a neurobehavioral assessment (locomotor activity, anxiety, working memory, special reference memory, visiospatial memory), imaging (tesla MRI 7, positron emission tomography), and immunohistochemistry at different time from 1,5 months to 12 months post-surgery.An initial WT mice cohort assessed at 6 weeks post-surgery demonstrated an impact of CMH on anxiety, spatial reference and visuospatial memory. An improvement in cognition performances was depicted under atorvastatin indicating this CMH-model is sensitive to pharmacological modulation.A longitudinal follow-up on WT and APP groups was performed assessing cognitive performances at 1.5, 3, 6, 9 and 12 months post-surgery. In WT mice, the CMH group showed a decreased level of anxiety and an impaired spatial reference memory at 1.5 months. Cognitive impairment was also found at 9 and 12 months in this group. This study did not allow to conclude in a precipitating or aggravating effect of the CMH in APP mice. The treatment by atorvastatin seemed to have a positive effect on cognition in both WT and APP mice. A decreased volume of ipsilateral hippocampus was observed in all APP and WT groups at 12 months. No difference in metabolism of brain structures was found.It is hypothesized that either the presence of CMB or the cerebrovascular damages underlying their occurrence may cause cognitive impairment. This study proved that isolated CMH can affect cognitive functions in WT mice, regardless of any underlying vascular pathology. It is likely that the burden of neurodegenerative lesions exceeds the cognitive impact of the CMH in APP mice. Atorvastatin seems to have a neuroprotective effect

La thrombolyse intraveineuse (TIV) est le seul traitement médical autorisé à la phase aiguë de l’infarctus cérébral (IC). Malgré ce traitement, un patient sur deux présente un mauvais pronostic fonctionnel à 3 mois (score mRS&gt;2), ce qui s’explique le plus souvent par l’absence de recanalisation précoce ou la survenue d’une hémorragie intracrânienne symptomatique (sICH). Nos objectifs étaient, d’une part, de déterminer s’il est possible d’estimer le pronostic fonctionnel (mRS) 3 mois après TIV à partir de variables cliniques et IRM disponibles à l’admission, et, d’autre part, d’étudier les relations entre l’évolution au cours des premières 24 heures et le mRS à 3 mois. Nous avons collecté les données cliniques et d’IRM de l’ensemble des patients traités par TIV pour un IC≤4h30 entre 2003 et 2015 à l’hôpital Sainte-Anne. (1) Nous avons proposé le score MRI-DRAGON, un outil simple basé sur 7 variables cliniques et IRM disponibles à l’admission, qui permet une prédiction satisfaisante du mRS&gt;2. 3 mois après un IC traité par TIV (c=0,83 [0,78-0,88]). (2) Nous avons ensuite réalisé une validation externe de ce score sur la cohorte du CHRU de Lille, confirmant qu’il présente une discrimination et une calibration satisfaisantes, malgré une surestimation du risque de mRS&gt;2 en cas de score MRI-DRAGON élevé. (3) Afin d’essayer d’améliorer la prédiction, nous avons étudié les relations entre microsaignements (CMBs) sur l’IRM initiale et pronostic fonctionnel, et montré que le nombre de CMBs n’était pas un prédicteur indépendant du mRS à 3 mois, après ajustement sur les facteurs de confusion (âge, HTA). Nous avons par ailleurs étudié les relations entre l’évolution clinique très précoce après TIV et mRS à 3 mois, à partir de deux situations: (4) Premièrement, l’absence d’amélioration neurologique 1 heure après le début de la TIV en cas d’occlusion artérielle proximale, présente chez 77% des patients et fortement associée au mRS à 3 mois, mais qui n’améliorait pas la prédiction par rapport au score MRI-DRAGON. (5) Deuxièmement, l’aggravation neurologique survenant dans les 24 heures après le début de la TIV (END), dont l’incidence au sein de notre revue systématique était de 14%. (6) Au sein de notre cohorte, la valeur prédictive positive de l’END pour le mRS&gt;2 à 3 mois était de 90%. L’END de cause indéterminée représentait 70% des END, et était associé à l’absence d’antiplaquettaire avant l’admission, la présence d’une occlusion artérielle proximale, d’un important mismatch diffusion-perfusion, et l’absence de recanalisation. Nous avons proposé un score simple permettant de prédire dès l’admission le pronostic fonctionnel à 3 mois d’un patient traité par TIV pour IC aigu. Il pourrait être utilisé pour guider la décision thérapeutique en identifiant les patients ayant une forte probabilité de mRS ≤2 après TIV seule. Par ailleurs, notre travail suggère que la prise en compte des CMBs avant TIV ne permet pas d’améliorer la prédiction pronostique, et que l’association entre CMBs et mRS n’est pas indépendante. Nous participons actuellement à une méta-analyse internationale sur données individuelles visant à déterminer si un sous-groupe de patients avec CMBs présente un risque de sICH si important qu’il pourrait annuler le bénéfice attendu de la TIV. Bien que l’absence d’amélioration neurologique à 1 heure soit fortement associée au mRS&gt;2 à 3 mois, elle ne semble pas être un outil suffisamment robuste pour guider la décision d’une thrombectomie complémentaire à la TIV (bridging therapy), et ne doit donc pas retarder le geste endovasculaire. Enfin, nos résultats suggèrent que la majorité des END sont favorisés par la persistance d’une hypoperfusion cérébrale, et qu’une part d’entre eux pourrait être prochainement évitée, depuis la démonstration fin 2014, de la nette supériorité du bridging therapy par rapport à la TIV seule concernant la recanalisation artérielle. (...)<br>Intravenous thrombolysis (IVT) is the only licensed drug for acute ischemic stroke (AIS). However, about half of the treated patients do not achieve functional independence at 3 months (mRS&gt;2), mostly due to lack of early recanalization or symptomatic intracranial hemorrhage (sICH). Firstly, we aimed to determine if 3-month outcome (mRS) after IVT can be reliably predicted based on clinical and MRI variables available at admission. Secondly, we assessed the relationships between the clinical course within 24 hours after IVT and 3-month mRS. We collected clinical and MRI data of all patients treated by IVT ≤4.5 hrs for AIS between 2003 and 2015 in Sainte-Anne hospital, Paris. (1) We derived the MRI-DRAGON score, a simple tool consisting of 7 clinical and MRI variables available at admission, which can reliably predict 3-month mRS&gt;2 (c-statistic=0.83 [0.78-0.88]). (2) We then performed an external validation of this score in the Lille cohort, showing good discrimination and calibration of the model, despite an overestimation of the risk of mRS&gt;2 in patients with a high MRI-DRAGON score. (3) Trying to find additional predictors of long-term outcome, we showed that the cerebral microbleed (CMB) burden at baseline was not an independent predictor of 3-month mRS after adjusting for confounding factors (age and hypertension).Furthermore, we assessed the relationships between early clinical course after IVT and 3-month mRS, based on two common clinical events: (4) Firstly, the lack of very early neurological improvement (VENI) 1 hour after IVT, which was observed in 77% patients and strongly associated with 3-month mRS, but did not improve the predictive ability of the model when incorporated into the MRI-DRAGON score. (5) Secondly, early neurological deterioration (END) within 24 hours after IVT, occuring in 14% patients in our systematic review and meta-analysis. (6) In our cohort, the positive predictive value of END for 3-month mRS&gt;2 prediction was 90%. END of undetermined cause (ENDunexplained) accounted for 70% of ENDs, and was associated with no prior use of antiplatelets, proximal artery occlusion, DWI-PWI mismatch volume and lack of recanalization. We proposed a simple score to predict 3-month mRS soon after admission in patients treated by IVT for AIS. It may be used to help therapeutic decisions, by identifying patients likely to achieve 3-month mRS ≤2 after IVT alone. We have also shown that CMB burden before IVT is not an independent predictor or 3-month outcome. We participate in an ongoing international individual patient data meta-analysis to determine whether there is a subgroup of patients with CMBs, which seems to have an independent risk of poor 3-month outcome so important that it might outweigh the expected benefit of IVT. Although lack of VENI 1 hour after IVT is strongly associated with 3-month mRS&gt;2, it doesn’t seem to be specific enough to guide decision-making regarding additional thrombectomy (bridging therapy), and should therefore not delay an endovascular procedure. Finally, our results suggest that a persistent cerebral hypoperfusion contributes to most ENDs. Therefore, many ENDs might be avoided in a near future, given the recent proof of the clear superiority of bridging therapy over IVT alone regarding recanalization. This revolution in acute stroke management leads the way to important clinical research perspectives, such as developing a tool to accurately predict 3-month mRS after bridging therapy. Important research efforts will be needed to develop a personalized treatment algorithm, helping to determine which therapeutic option (bridging therapy, IVT alone, thrombectomy alone, or no recanalization therapy) would be the best for each patient

Les microhémorragies cérébrales (MHC), petites lésions dont la prévalence augmenteavec l’âge sont associées à un risque augmenté de troubles cognitifs. Les mécanismes parlesquels les MHC pourraient altérer les fonctions cognitives ainsi que l’effet du sexe sur lesMHC ne sont pas bien élucidés. Le premier objectif de ce travail de thèse était d’étudier lesmécanismes mis en place après la formation d’une MHC corticale, chez des souris mâles etfemelles. Le deuxième objectif était de déterminer les effets de l’atorvastatine, médicamentconnu pour ses effets pléïotropes, sur la cognition et sur les mécanismes induits par la MHC.Six semaines après la formation d’une MHC induite par injection stéréotaxique de collagénasedans le cortex de souris C57BL/6J, des effets différents en fonction du sexe d’ordre cellulaire,protéique, génomique et métabolique étaient observés dans le cortex et l’hippocampe des sourismâles et femelles, conduisant à l’hypothèse d’une altération des réseaux corticohippocampiques,à l’origine de troubles de la cognition chez les mâles. L’atorvastatinecorrigeait les modifications induites par la MHC en fonction du sexe et améliorait les troublesde la cognition chez les mâles. Au total, cette étude a montré, à partir d’un travail précis portantsur l’impact cognitif d’une MHC, que la prise en compte du sexe dans un protocole précliniques’avère indispensable pour mieux élucider les mécanismes physiopathologiques de la maladiemodélisée dans le but de développer des traitements les plus adaptés possibles<br>Cerebral microhemorrhages (CMH) are small lesions whose prevalence increases withage. CMH are associated with a risk of cognitive impairment. The mechanisms by which CMHimpair cognitive function and an eventual sex effect on CMH remain under-explored. The firstgoal of this work was to characterize the mechanisms induced by a cortical CMH, in male andfemale mice. The second objective was to determine the effects of atorvastatin (AT), a drugknown for its pleiotropic effects, on those mechanisms and on cognition. Six weeks after theformation of a CMH, induced by an injection of collagenase in the cortex of C57BL/6J mice,sex-specific cellular, protein, genomic, and metabolic modifications were observed in thecortex and hippocampus of male and female mice, suggesting an impairment of the corticohippocampalnetwork explaining the cognitive impairment in males. AT has modified theCMH-induced sex-specific modifications and has improved cognition in males. This studyhighlights the necessity to take sex into account in preclinical studies to increase ourcomprehension of pathophysiological mechanisms and develop the most appropriate treatment

碩士<br>中原大學<br>生物醫學工程研究所<br>103<br>The relation between Cerebral Microbleed (CMB) and neurological diseases has been verified, and the physicians calculate the number and surface areas of micro bleeding points by means of diagnosing MRI images. Thus, the purpose of this research is to develop a computer-aided detecting system (CAD) for reducing the time of diagnoses and quantifying the significant parameters during diagnosis. First of all, we utilized region growing method to get rid of the information beyond cerebral tissues. Secondly, we identified the low frequency micro bleeding points by the threshold method, and then manually eliminate extra image information. Third, after the physicians manually selected the bleeding and calcified points, we figured out the significant parameters through T-test and support vector machine (SVM), furthermore, compared the result of our CAD system with pathological reports to evaluate the performance of this CAD system. Fourth, we manually removed the tissues beyond the bleeding points for avoiding the system errors. Finally, the volume of bleeding points was evaluated by the means of stacking up all the surface areas of bleeding points together by region of interest (ROI) method. In this study, we use 40 images which including 107 ROI points (81 bleeding points and 26 calcified points) were used to evaluate the performance of our CAD system and 20 images and 20 images were used as train set and test set. The result shows that the differences between system selection and physician manual selection as below: the error rates of the surface areas are 4.98%. The system to features analysis for cerebral microbleed and calcified points and get the result as: for train set the sensitivity, accuracy, specificity, and Kappa value is 100%, 96.3%, 84.6%, and 0.94; for test set the sensitivity, accuracy, specificity, and Kappa value is 100%, 98%, 92.3%, and 0.95, respectively. To sum up, the developed CAD system in this study can process and diagnose the MRI images with CMB; in addition, calculating the number, surface area and volume of bleeding points are available in this CAD system as well. As a result, reduced the diagnoses time and provide physicians with objective information, and also help doctors to diagnose more precisely. In the future, we hope there are more MRI images that allow us to improve the preciseness of the CAD system, and also find the correlation between the neurological diseases and the position of bleeding points. Moreover, we also look forward to decorate the CAD system become a fully automatic one and provide the reliable information immediately. We believe that this technique will be applied in clinical medicine in the near future for improving the quality and efficiency of medicine.

Approximately 7 – 9 % of the population is living with some form of diabetes. When poorly controlled (which is often the case), this disease is associated with cerebrovascular pathology such as microbleeds and impairments in cognitive function. The presence and burden of microbleeds in the brain has been strongly linked with cognitive decline and increased risk of dementia. Microglia, the resident immune cells of the central nervous system, dynamically respond to vascular insults by extending their processes to the site of injury. The rapid actions of microglia are thought to play a beneficial role in vascular repair since inhibiting these responses can exacerbate injury. Here, we hypothesized that diabetes, especially if not well controlled with insulin, will disrupt microglia responses to damaged microvessels in the brain which will lead to increased plasma leakage from damaged microvessels. Using two-photon in vivo imaging, we show that chronic hyperglycemia in the streptozotocin model of type one diabetes leads to decreased microglial process accumulation around the site of microvascular injury and increased permeability of fluorescent dyes from the damaged vessel 30 minutes after induction of the bleed. Importantly, this impaired microglial and vascular response could be partially mitigated with tight control of blood glucose levels with insulin. These results indicate that chronic hyperglycemia disrupts microglial based repair of damaged microvessels, which may help explain why poorly controlled diabetes is associated with greater a risk of cerebrovascular dysfunction and cognitive decline.<br>Graduate<br>2018-01-12

Previous studies have shown the connection between aortic stiffness, cerebral microbleeds (CMBs) and increased cognitive decline in both human and mouse studies (Akoudad et al., 2016; Mitchell, 2015; Wang, 2018). However, most studies have been done only on males, leaving out a clear understanding of sex differences in CMBs. The purpose of the present study is to identify the changes in CMB levels in aging C57BL/6 female mice and compare this to the aging male mouse model. There were two hypotheses the study aimed to test: (1) female mice would show an increase in CMBs with age and (2) the level of CMBs in females would be less than in males until old age where both sexes will have similar levels of microbleeds. To test the hypotheses, histology via Prussian Blue staining was used to detect CMBs in the perfused C57BL/6 aging female mice and then compared to CMB levels in the males, found previously (Wang, 2018). The results support the first hypothesis that CMBs increase with age in the female mouse model. However, the level of CMBs is decreased in the old age female compared to the old male. The present study is the first to show sex differences in cerebral microbleeds with age. This is relevant to researchers and clinicians as it shows that sex differences need to be accounted for when identifying mechanisms and developing cures for diseases such as dementia.<br>2021-06-18T00:00:00Z

Traumatic Brain Injury (TBI) is a growing global health problem. Mild forms of TBI (mTBI) such as concussions, represent the most common manifestation of this type of injury with children and youth (< 20 years old) among the most likely to sustain mTBI. There is growing evidence for the cumulative effects of repeated mTBI (rmTBI) suggesting that while a single concussion may not cause evident or long-lasting brain alterations, the summation of multiple mTBI may lead to more severe consequences. In contrast to severe TBI, lesions in mTBI patients are challenging to detect. Despite this, mTBI patients may still present with cognitive and emotional deficits. Cerebral microbleeds (CMBS), a subtle form of vascular damage, have been identified as an early hallmark in brain trauma and several neurodegenerative diseases. The cumulative effects of subtle but sustained microvascular damage could explain the persistent long-term functional deficits observed in mTBI. In this study, the awake closed-head injury (ACHI) model was used to investigate the association between rmTBI and microvascular damage in different brain regions in both male and female juvenile rats at one and seven days after the last injury. The results indicate that the injury paradigm used in this study (i.e. 8 impacts over 4 days) using the ACHI model is associated with an acute increase in sings of microvascular damage in both sexes that is no longer evident at a longer time point. These study is the first to describe the negative impact of rmTBI on CMBs in the juvenile using an awake animal model, and provides evidence for the potential involvement of this subtle form of vascular damage in the development of neurological deficits after rmTBI.<br>Graduate

碩士<br>中原大學<br>生物醫學工程研究所<br>102<br>Abstract The purpose of this study is to develop a computer aided system for Carotid plaque which can obtain the cerebral microbleeds information from ultrasound image. A cerebral micro-bleeds (CMBs) has a tight connection between both the stroke and the treatment of Acute Stroke. However, doctors could only currently diagnose the CMBs through the Magnetic resonance imaging (MRI) Scanning, which is impossible for the urgent patients, and thus raise the probability of complication caused by those treatments. The Carotid Ultrasound(US) image is easy to obtain in non-invasive way, but it is noisy. Histogram equalization method used to enhance the image characteristics after taking the initial segmentation of carotid with the region growing, which offer doctors great conveniences to choose the region of interest (ROI). After the selection, the grayscale distribution of ROI was analyzed, and then statistic of the differences of spectral parameters between CMBs and non-CMBs was calculated. Those different parameters were selected for the image classifications. Totally 20 patients’ US images were used to test this system and are divided into two parts, one stand for the normal group while the other ten are CMBs ones. In each patient’ image was classified as Intimal-Medial Thickness (IMT) region and plaque region which are 29 and 69 regions, respectively. When classification model was trained by Support vector machine (SVM), the system would classified the image and the result would verify by compared with the standard which was diagnostic by doctor through the MRI image. The result show that, in those plaque region case, two parameters (lipids proportion and calcification proportion) are most significant differences (p<0.05) in CMBs symptom. Kappa values for system with classified by lipids proportion only and calcification proportion only are 0.557 and 0.424, respectively. Yet kappa value will reach the normal consistent as 0.614 when two parameters are both used for classification. In IMT images case, another two parameters (narrow ratio and fiber proportion) have significant differences. Kappa value is 0.586 when both of the parameters were conducted to the classification, which has reached the normal consistent. Synthesize the results, our system can assist doctors to diagnostics the possibility of CMBs by Ultrasound images and the automated classification effect are normal consistent compare to MRI images. It confirms that our system can provide the information for cerebral microbleeds and the classification result can become a reference to diagnostic by Physician.

碩士<br>中原大學<br>生物醫學工程研究所<br>101<br>Non-contrast Computed Tomography (NCCT) images cannot provide detailed information on the clinical diagnosis in detecting cerebral microbleeds. In order to avoid risk of hemorrhagic transformation during thrombotytic or antithrombin therapy, clinicians must be carefully to assess the treatment for patients with cerebral microbleeds. Therefore, the purpose of this study was to assess cerebral microbleeds on non-contrast CT images with image processing techniques, and find statistically significant parameters by texture analysis, and move further to provide a reference of future research. In this study, firstly, image pre-processing was used to extract brain tissue, and then brain images enhanced through logarithmic transformation, Gamma transformation and histogram equalization, also compared it to highlight the effect of microbleeds lesions. Followed by ROI manually selecting of the lesion and non-lesion, and then neighboring gray level dependence matrix and gray level co-occurrence matrix were used as texture analysis. Furthermore, 10 regions of interest (ROIs) as lesions and 20 ROIs as non-lesion were selected, and extracted the 30 texture parameters by statistics. Finally, 6 original images and 6 enhanced images were provided to assess the lesion through questionnaire by specialist physicians in this study. The results show that histogram equalization was the best enhancement in this study. In texture analysis part, the results of statistics show that Contrast_0, Homogeneity_0, Homogeneity_90, and Homogeneity_135 were statistically significant in lesion classification when the size of lesion was similar to non-lesion; the NNU, SM, EN, Homogeneity_0, Homogeneity_90, and Homogeneity_135 were statistically significant in lesion classification when the size of lesion were not similar to non-lesion. In addition, some brain due to old hemorrhage caused by the ROI selected would produce error, the maximum of error rate was 22.43%. Therefore, after excluding this error, the results of statistics show that Energy_135, Entropy_0, Entropy_45, Entropy_90, and Entropy_135 are statistically significant in lesion classification. This study provided specialist physicians enhanced images as microbleeds lesions selecting and the best accuracy rate of detection was 85.71%. In summary, this study could detect cerebral microbleeds on non-contrast CT images with histogram equalization and find statistically significant texture parameters. This study is positively helpful to provide future research of aided detection as a reference.

Microglia and brain-resident macrophages are the sentinel immune cells of the central nervous system (CNS), and are ideally situated to respond to any damage to the brain parenchyma or vasculature. Circulating leukocytes are generally excluded from the CNS environment under homeostatic conditions but can gain access to this region in diseases that disrupt immune system function and blood-brain barrier integrity. Although these diverse immune cells exhibit properties that may engender them to be well-suited to resolve microcirculatory insults, their relative contributions to the recanalization of capillary rupture in the cortex, known as cerebral microbleeds (CMBs), has yet to be described. CMBs are particularly concerning in conditions, such as diabetes mellitus (DM), in which these insults occur more frequently and potentially underlie the onset and progression of cognitive decline. Using in vivo 2-photon microscopy and confocal imaging, here I highlight the compromised repair of CMBs in a mouse model of type 1 DM and characterize the robust, heterogeneous macrophage response to these insults. Specifically, 20% of damaged capillaries were eliminated from the circulation in the diabetic cortex and chronic insulin treatment failed to prevent this microvascular loss. Administration of interferon-α or interferon-γ neutralizing antibodies to dampen inflammatory signalling, or dexamethasone to reduce global inflammation, also failed to improve repair rates of damaged microvessels in diabetic mice. In contrast, CMBs in nondiabetic mice repaired without exception. Interestingly, depletion of CNS macrophages using the colony stimulating factor-1 receptor antagonist PLX5622 resulted in microvascular elimination in nondiabetic mice. Given the robust depletion of brain macrophage populations with this treatment, at first these data suggested that these cells were necessary for microvascular repair since their elimination produced vessel loss. However, by parsing the data I identified that microvessels repaired in all cases where macrophages were not identified at the CMB; when CX3CR1+ aggregate was localized to the injury, ~20% of microvessels were eliminated. These findings show that CNS macrophages are not required for microvascular repair following CMB. Immunofluorescent co-labelling of various microglial and macrophage markers within the diabetic CMB milieu revealed a novel population of Mac2+/TMEM119- cells, distinct from homeostatic TMEM119+ microglia. These cells reliably localized to CMBs that failed to repair and rarely associated with vessels that recanalized; Mac2+/TMEM119- cells were not found within nondiabetic CMBs. Treatment of diabetic mice with clodronate liposomes (CLR) to deplete circulating phagocytic leukocytes prevented aggregation of Mac2+/TMEM119- cells to CMBs and improved capillary repair rates. The efficacy of CLR in excluding these cells from the CMB aggregate, coincident with eradication of monocytes from circulation, indicated that these cells likely arose from the periphery. In vivo 2-photon imaging revealed significant increases in lipofuscin at the site of diabetic CMBs relative to the nondiabetic context; other phagocytic markers including CD68 and TREM2 were also upregulated. Mac2+/TMEM119- cells showed elevated lipofuscin content relative to homeostatic microglia; their association with CMBs may thus signal an increase in phagocytosis that contributes to capillary pruning. Taken together, these data identify a novel Mac2+/TMEM119- macrophage associated with pathological microvascular elimination following CMB in the diabetic neocortex. These findings highlight the diversity of immune cell responses to CNS injury and provide insights into the cellular mechanisms of capillary pruning. Furthermore, these advances in our understanding of the regulation of microvascular elimination in the diabetic brain may have clinical implications for patients with DM as they provide evidence for putative adjuvant anti-inflammatory treatments, such as CLR, in mitigating cerebrovascular pathology.<br>Graduate<br>2022-05-06