Background Lacunar ischaemic stroke accounts for around one quarter of all strokes, and is presumed to result from the occlusion of a single perforating artery supplying the deep subcortical areas of the brain. The underlying arterial pathology is poorly understood, but is thought to differ from the atherothrombotic processes that occlude larger intra- and extracranial arteries causing most other ischaemic stroke subtypes. Progress in understanding the aetiology of lacunar stroke has been limited by the lack of informative autopsy studies, and the difficulties in studying small blood vessels using brain imaging. One alternative approach is to compare the epidemiology of ischaemic stroke subtypes, since differences in the epidemiology may reflect and inform about different underlying pathologies. Methods I performed two systematic literature reviews to identify studies presenting data on (1) the risk factors for, and (2) the outcome of, different ischaemic stroke subtypes. I extracted relevant data from included studies and performed a series of meta-analyses comparing risk factor profiles, and risks of death, recurrent stroke and myocardial infarction (MI) in patients with lacunar versus non-lacunar ischaemic stroke. To address some of the unanswered questions and controversies surrounding the causes of ischaemic stroke we set up the Edinburgh Stroke Study (ESS), which I co-ordinated. We recruited patients with stroke and transient ischaemic attack seen at our hospital between 2002 and 2005, and followed them for 1-4 years for death, recurrent stroke and MI. To overcome the methodological limitations of the studies included in my reviews and of my meta-analyses, I carried out a large collaborative individual patient data analysis in which I combined data from five stroke registries - including the ESS - that had used similar robust methodology, and performed a series of analyses comparing the risk factor profiles of patients with lacunar versus nonlacunar ischaemic stroke. In an updated meta-analysis, I combined this data with existing published studies that had used an unbiased method of classifying ischaemic stroke subtypes. Using the ESS data, I compared the risks of recurrent stroke and MI, and patterns of recurrent stroke subtypes in patients with lacunar versus nonlacunar stroke. Results In my systematic review of risk factors I found evidence of classification bias in many studies, where systematic error was introduced through the use of classification methods that included risk factors in the definitions of stroke subtypes. This led to overestimation of some risk factor-stroke subtype associations and, in particular, to apparently stronger associations between hypertension and diabetes and lacunar compared with non-lacunar ischaemic stroke. When I included only unbiased studies, I found a significantly reduced prevalence of atrial fibrillation (AF) and severe carotid stenosis and a trend towards a reduced prevalence of ischaemic heart disease (IHD) in lacunar patients. I found a very slight excess of hypertension among lacunar patients, but no difference in the prevalence of diabetes, or any other risk factor studied. In my collaborative individual patient data analysis, I confirmed a significantly lower prevalence of severe carotid stenosis, AF and previous IHD in patients with lacunar ischaemic stroke, but found no difference in the prevalence of hypertension, diabetes, or any other risk factor studied, even after adjusting for confounding factors. These results were largely confirmed in my updated metaanalysis, although there was a slight excess of hypertension among lacunar compared with non-lacunar ischaemic strokes. In my systematic review of outcome after lacunar versus non-lacunar ischaemic stroke, I found a lower risk of death following lacunar compared with non-lacunar stroke which attenuated but persisted long-term; a higher recurrent stroke risk in non-lacunar patients during the first month only; and limited data on recurrent stroke subtypes suggesting that ischaemic stroke subtypes may breed true to type. Data on MI risk were extremely sparse. My analyses of data from the ESS showed no difference overall in risk of recurrent stroke between patients with lacunar versus non-lacunar ischaemic stroke, but some evidence for a lower very early recurrence risk among lacunar patients. There was evidence that recurrent stroke subtypes breed true, since patients with a lacunar stroke at baseline were much more likely to have a lacunar than a non-lacunar recurrence. We identified five times as many MI events following stroke than have been previously reported in the published literature, and found a non-significantly reduced risk of MI in patients with lacunar compared with non-lacunar ischaemic stroke. Conclusions My comparisons of the epidemiology of lacunar versus non-lacunar ischaemic stroke subtypes revealed differences in the risk factor profiles and risks of recurrent stroke and myocardial infarction which suggest that a distinct, nonatherothrombotic arteriopathy underlies many lacunar ischaemic strokes. My analyses of recurrent stroke subtype patterns suggest that recurrent ischaemic strokes subtypes tend to breed true, providing further support for a distinct lacunar arteriopathy. Contrary to widespread belief, hypertension and diabetes do not appear to be more important in the aetiology of lacunar stroke than in other types of ischaemic stroke. These findings support other lines of evidence for a distinct lacunar arteriopathy, and highlight the need for further research into the aetiology of lacunar ischaemic stroke.

BACKGROUND: Under the current treatment guidelines for acute ischemic stroke, intravenous alteplase may be used within 3-4.5 hours of symptom recognition or in cases of unknown onset if there is a small lesion on diffusion weighted imaging without increased signal on FLAIR sequence MRI. We seek to determine whether patients with lacunar strokes greater than 4.5 hours post onset with a DWI-FLAIR mismatch on imaging will benefit from thrombolysis with intravenous alteplase. METHODS: We will conduct a multicenter, randomized, double-blinded, placebo-controlled trial of patients presenting with acute ischemic stroke within 4.5 to 6 hours of symptom onset with DWI-FLAIR mismatch and without a large vessel occlusion. A target of 682 patients will be randomized to receive IV alteplase or placebo. The primary outcome is a favorable functional status as defined by a score of 0 or 1 on the modified Rankin scale (mRS) at 90 days. The secondary outcome is ordinal score on the modified Rankin scale at 90 days. The primary safety end points will be symptomatic intracranial hemorrhage (sICH) and death CONCLUSIONS: If intravenous (IV) alteplase is found to be an effective and safe treatment for lacunar stroke with DWI-FLAIR mismatch >4.5 hours from onset, these patients could have significantly reduced morbidity and improved long-term outcomes.

Cerebral small vessel disease (SVD) is a distinct microvascular disorder that can lead to lacunar stroke, an important stroke subtype that accounts for a quarter of all ischaemic strokes. SVD is associated with imaging biomarkers such as white matter hyperintensities (WMH). The cause of SVD is largely unknown, although inflammation and blood-brain barrier failure via endothelial dysfunction have been implicated. Elevated plasma biomarkers of inflammation are associated with coronary heart disease and large vessel stroke but the role of inflammation in SVD is less well understood. Our hypothesis is that inflammation plays a role in SVD and we sought to examine this by reviewing the literature for evidence of this, and by conducting a brain imaging study of patients with a known inflammatory disease and reviewing the images for evidence of inflammation and SVD, and comparing findings with controls groups. Section A: This thesis begins with a systematic review and meta-analysis of 13 plasma biomarkers of four physiological processes (coagulation, fibrinolysis, endothelial dysfunction and inflammation) in lacunar stroke versus non-lacunar stroke (to control for having any stroke) and non-stroke (to compare to the general population). We sought to know if there were differences in these biomarkers between lacunar stroke and other stroke subtypes and non-stroke controls as a way of generating hypotheses for the disease mechanisms that might lead to lacunar stroke. Findings revealed differences in several biomarkers between lacunar stroke and healthy controls but only fibrinogen, D-dimer, von Willebrand factor and interleukin-6 were different (all significantly lower in lacunar stroke) between lacunar stroke and other stroke subtypes. There was heterogeneity between studies, including variations in the definition of lacunar stroke and most studies measured the biomarkers in the acute phase post stroke, which is potentially confounding. To further examine plasma biomarkers of inflammation and endothelial dysfunction in SVD, we used data from a prior study of mild stroke conducted at the Brain Research Imaging Centre, University of Edinburgh, UK. Lacunar stroke patients were compared to cortical stroke patients. The lacunar group had lower levels of tissue plasminogen activator independent of age, sex and vascular risk factors but we found no difference in the other plasma biomarkers. Section B: Non-resolving systemic inflammation is a feature of inflammatory autoimmune rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). These patients are at increased risk of stroke but much knowledge relates to stroke in general; less is known about associations with stroke subtypes including SVD, or when in life stroke risk is greatest. Consequently, we sought to better understand the influence of inflammatory rheumatic diseases on stroke and SVD. The review and meta-analysis of cerebrovascular disease in rheumatic diseases showed an excess risk of stroke in RA, SLE, ankylosing spondylitis, gout and psoriasis over the general population. Meta-analyses of stroke subtypes (ischaemic and haemorrhagic) in RA and SLE showed an excess risk of stroke over the general population. Stroke risk across rheumatic diseases was highest in those aged < 50 years and reduced with ageing. We then requested data from NHS Lothian covering 15 years so that we could assess stroke, including stroke subtypes, among patients diagnosed with various arthropathies. We linked 6,613 rheumatology patients’ records with stroke admission records, grouped the various rheumatic diseases into the two main types of arthritis, inflammatory and non-inflammatory, and also compared the strokes in these rheumatology patients to general population data. There was no difference in stroke prevalence between inflammatory and degenerative (non-inflammatory) arthropathies, although the strokes occurred up to two decades earlier than in the general population. Section C: Lastly, we conducted MRI neuroimaging in patients with SLE and reviewed and meta-analysed diffusion tensor imaging (DTI) (an imaging technique used to assess sub-visible white matter microstructure damage) in SLE to place our findings into context. The research question here was to ascertain if patients with a known inflammatory disease had brain imaging evidence of SVD, and to compare findings to controls. We compared imaging markers of SVD and DTI between SLE patients and age-matched healthy controls and sought associations between the imaging biomarkers and plasma biomarkers of inflammation and endothelial dysfunction, measures of fatigue and cognition, and scores of rheumatic disease activity. Fifty-one patients were recruited. There was higher mean diffusivity in all white matter tracts versus controls indicating a diffuse increase in brain water mobility in SLE. Meta-analysis confirmed higher mean diffusivity in SLE patients versus controls. Fatigue in SLE was significantly higher than a normal reference range and was associated with depression, anxiety, higher body mass index, lower mean diffusivity and some blood markers of inflammation and endothelial dysfunction. The most fatigued were youngest which explained the association with lower mean diffusivity. Damage to the brain’s white matter microstructure may be accelerated in SLE as the age-related declines in the general population are normally seen much later in life. The aging pattern is consistent with inflammation-related microvascular-mediated brain damage where the inflammation is systemic in origin. Summary: This thesis has demonstrated an increase in SVD burden in the inflammatory rheumatic disease SLE and increased stroke risk at younger ages in other inflammatory rheumatic diseases. Thus, systemic inflammation as seen in inflammatory rheumatic diseases could have effects on the brain directly, including influencing stroke risk which is clinically noteworthy and would benefit from further testing in appropriately designed studies such as an inception cohort that follows inflammatory rheumatic patients from diagnosis, with regular brain imaging to track brain changes and correlates with inflammatory profiles and impact on cognition.

Introduction: Lacunar strokes are both common and disabling; they cause up to 52 strokes per 100,000 people per year and 29-46% of survivors are disabled. Lacunar stroke is part of the spectrum of small vessel disease (SVD) which also causes cognitive impairment and gait disturbance; together these lead to dementia, falls and disability. Current evidence suggests that SVD is caused by a separate aetiology from large vessel stroke, which may be mediated by blood brain barrier (BBB) permeability and may affect organs other than the brain. We set out to establish whether SVD is a multi-system disorder of primary endothelial function, with leakage of blood-brain barrier leading to lacunar stroke, disability, and cognitive impairment. Methods: We recruited 264 patients with a lacunar or cortical stroke (118 lacunar, 146 cortical). All patients received baseline assessment of clinical features, magnetic resonance imaging (MRI), renal function, and assessment of dietary salt. At 1-3 months post-stroke we carried out cognitive testing and contrast MRI to assess blood-brain barrier integrity. We followed patients up at 12 months post-stroke with repeat cognitive testing, MRI, and assessment of disability and recurrent stroke. Results: We established that lacunar stroke has a different risk factor profile to cortical stroke, confirming findings from previous cohorts, but adding dietary salt as a risk factor for lacunar stroke and other SVD features. We confirmed that patients with a clinical stroke who did not have a lesion on diffusion-weighted MRI had the same clinical outcomes at 1 year post-stroke as those patients who did have a lesion. We established that patients who have a lacunar stroke are at as high a risk of post-stroke cognitive impairment as those with a cortical stroke. We found that blood brain barrier leakage predicted cognitive impairment at one year after lacunar and cortical stroke. We established the rates of disability and cognitive impairment at one-year post-lacunar stroke to estimate the required sample size for future trials. Conclusions: Taken together these findings confirm that lacunar stroke is part of a syndrome separate to large vessel stroke and may be mediated through blood brain barrier leakage. Dietary salt is an additional risk factor. The findings support further randomised controlled trials of treatments aimed specifically at lacunar stroke and lifestyle interventions including dietary salt reduction.

No description available.

Tendo como objeto de estudo a ficção de Cornelio Penna, representada por Fronteira (1935), primeiro livro do escritor, esta dissertação está estruturada em duas partes. Na primeira delas é desenvolvida uma breve abordagem do ambiente de 1930, com destaque para as tensões ideológicas e políticas que dominavam a cena. Nesse contexto, são relevantes as mudanças provocadas pela chegada de Getúlio Vargas ao poder e pelo rearmamento institucional experimentado pela Igreja desde a década anterior. Esse estado de coisas se refletiu na produção cultural e, no caso específico da literatura, foi percebido pela crítica como responsável pelo estabelecimento de uma polarização entre autores regionalistas e católicos/intimistas, reproduzindo de certa forma a oposição política existente entre direita e esquerda. O que se procura problematizar aqui é a rigidez dessa categorização, que, de modo sumário, acaba por misturar escritores de orientações muito diversas. Em última instância, questiona-se a própria validade do termo romance católico, que, em função de seus contornos pouco precisos, conduz facilmente a equívocos e generalizações. A segunda parte do trabalho consiste numa leitura de Fronteira. Explorando de modo profundamente original as possibilidades do realismo psicológico, Cornelio cria um romance que destoa no ambiente marcado por obras de cunho político e documental. Ambientada no século XIX, a narrativa exibe características muito peculiares, sobretudo no que toca ao ritmo lento e a uma premente ausência de explicações para os eventos descritos. Embora manipulando elementos de ordem histórica e social, o texto introspectivo de Cornelio se mantém formalmente distante da literatura de denúncia, sendo por vezes associado, de forma indevida, ao pensamento católico conservador. Partindo de aspectos específicos do romance, como a relação problemática que se estabelece entre os indivíduos e a impossibilidade de figurarem harmoniosamente num espaço que lhes é hostil e ameaçador, a análise pretende identificar marcas constitutivas e mecanismos ficcionais que permitam compreender melhor a lógica particular que rege o funcionamento do texto corneliano / Having as an object of study the fiction of Cornelio Penna, represented by his first book, Threshold (1935), this dissertation is structured into two parts. In the first one a brief approach to the political and ideological climate of the Thirties is developed. In this context, the changes occurred with the arrival of Getúlio Vargas to power and with the institutional rearmament that Church had been experimenting since the previous decade are relevant. This state of affairs had reflections on cultural production and was seen by literary criticism as responsible for the establishment of a polarization between regionalist and Catholic/intimist authors, reproducing, to some extent, the existing left-right political opposition. The intention here is to problematize the rigidness of this categorization, which, in a hurried manner, ends up mixing writers of extremely different orientations. In the last instance, what is questioned is the validity itself of the term Catholic novel, which, because of its vague delimitations, leads easily to mistakes and generalizations. The second part of the dissertation consists of a reading of Threshold. Exploring in a deeply original way the possibilities of psychological realism, Cornelio creates a novel that does not fit in the space dominated by works with documentary and political concerns. Set in the nineteenth century, the narrative shows some quite peculiar characteristics, especially when it comes to its slow rhythm and to an anguishing lack of explanations to the depicted events. Although manipulating social and historic elements, Cornelios introspective text keeps itself formally distant from literature of denunciation, being at times inappropriately associated with conservative Catholic intellectuality. Starting from specific aspects of the novel, such as the problematic relationship that is established among individuals and the impossibility of them harmoniously being part of a space which is in fact hostile and threatening, the analysis intends to identify constitutive marks and fictional mechanisms that allow a better understanding of the particular logic that governs the functioning of Cornelios text

Tendo como objeto de estudo a ficção de Cornelio Penna, representada por Fronteira (1935), primeiro livro do escritor, esta dissertação está estruturada em duas partes. Na primeira delas é desenvolvida uma breve abordagem do ambiente de 1930, com destaque para as tensões ideológicas e políticas que dominavam a cena. Nesse contexto, são relevantes as mudanças provocadas pela chegada de Getúlio Vargas ao poder e pelo rearmamento institucional experimentado pela Igreja desde a década anterior. Esse estado de coisas se refletiu na produção cultural e, no caso específico da literatura, foi percebido pela crítica como responsável pelo estabelecimento de uma polarização entre autores regionalistas e católicos/intimistas, reproduzindo de certa forma a oposição política existente entre direita e esquerda. O que se procura problematizar aqui é a rigidez dessa categorização, que, de modo sumário, acaba por misturar escritores de orientações muito diversas. Em última instância, questiona-se a própria validade do termo romance católico, que, em função de seus contornos pouco precisos, conduz facilmente a equívocos e generalizações. A segunda parte do trabalho consiste numa leitura de Fronteira. Explorando de modo profundamente original as possibilidades do realismo psicológico, Cornelio cria um romance que destoa no ambiente marcado por obras de cunho político e documental. Ambientada no século XIX, a narrativa exibe características muito peculiares, sobretudo no que toca ao ritmo lento e a uma premente ausência de explicações para os eventos descritos. Embora manipulando elementos de ordem histórica e social, o texto introspectivo de Cornelio se mantém formalmente distante da literatura de denúncia, sendo por vezes associado, de forma indevida, ao pensamento católico conservador. Partindo de aspectos específicos do romance, como a relação problemática que se estabelece entre os indivíduos e a impossibilidade de figurarem harmoniosamente num espaço que lhes é hostil e ameaçador, a análise pretende identificar marcas constitutivas e mecanismos ficcionais que permitam compreender melhor a lógica particular que rege o funcionamento do texto corneliano / Having as an object of study the fiction of Cornelio Penna, represented by his first book, Threshold (1935), this dissertation is structured into two parts. In the first one a brief approach to the political and ideological climate of the Thirties is developed. In this context, the changes occurred with the arrival of Getúlio Vargas to power and with the institutional rearmament that Church had been experimenting since the previous decade are relevant. This state of affairs had reflections on cultural production and was seen by literary criticism as responsible for the establishment of a polarization between regionalist and Catholic/intimist authors, reproducing, to some extent, the existing left-right political opposition. The intention here is to problematize the rigidness of this categorization, which, in a hurried manner, ends up mixing writers of extremely different orientations. In the last instance, what is questioned is the validity itself of the term Catholic novel, which, because of its vague delimitations, leads easily to mistakes and generalizations. The second part of the dissertation consists of a reading of Threshold. Exploring in a deeply original way the possibilities of psychological realism, Cornelio creates a novel that does not fit in the space dominated by works with documentary and political concerns. Set in the nineteenth century, the narrative shows some quite peculiar characteristics, especially when it comes to its slow rhythm and to an anguishing lack of explanations to the depicted events. Although manipulating social and historic elements, Cornelios introspective text keeps itself formally distant from literature of denunciation, being at times inappropriately associated with conservative Catholic intellectuality. Starting from specific aspects of the novel, such as the problematic relationship that is established among individuals and the impossibility of them harmoniously being part of a space which is in fact hostile and threatening, the analysis intends to identify constitutive marks and fictional mechanisms that allow a better understanding of the particular logic that governs the functioning of Cornelios text

Background. Lacunar strokes account for 25% of all ischaemic stroke but the exact nature of the causative cerebral small vessel abnormality remains unknown. Pathological studies are technically difficult and brain imaging cannot adequately characterise the cerebral small vessels. The retinal blood vessels are of similar size and physiology to the cerebral small vessels and may act as a surrogate marker for these cerebral small vessels. We therefore investigated retinal microvascular abnormalities in lacunar stroke. Methods. We performed a systematic review of retinal microvascular abnormalities in lacunar stroke to clarify associations and identify where further research was required. We then established a cohort of patients presenting with lacunar stroke with cortical stroke controls to investigate differences in retinal microvascular abnormalities between stroke subtypes. All patients had MRI brain at presentation and digital retinal photography of both eyes. We investigated the prevalence of retinopathy (hard and soft exudates or haemorrhages/microaneurysms), focal arteriolar narrowing and arteriovenous nicking . We developed, validated and used novel semi-automated techniques for measuring retinal arteriolar and venular widths, retinal arteriolar geometry (branching co-efficients (change in arteriolar cross sectional area across a bifurcation) and branching angles) and fractal dimensions (reflecting branching complexity) of the vasculature. We also assessed MRI parameters in lacunar stroke. We used multivariable analysis to correct for baseline imbalances in vascular risk factors. Results. From the systematic review we demonstrated that retinal microvascular abnormalities are associated with incident and prevalent stroke but that in general, strokes were inadequately characterised and there were no data regarding retinal microvascular abnormalities in ischaemic stroke subtypes. We recruited 253 patients, 129 lacunar strokes and 124 cortical strokes, mean age 68 years. We found no difference in the prevalence of retinopathy, arteriovenous nicking, focal arteriolar narrowing or arteriolar widths between lacunar and cortical stroke subtypes. We found that venules were wider in lacunar stroke. We found no differences in arteriolar branching co-efficients or arteriolar branching angles between lacunar and cortical strokes but found that deep white matter white matter hyperintensities on MRI were associated with increased branching co-efficients and periventricular white matter hyperintensities associated with decreased branching co-efficients. We found that the fractal dimension of the vascular tree was decreased in lacunar stroke. Furthermore we found that enlarged perivascular spaces on MRI are associated with lacunar stroke and white matter disease. Conclusions. We have clearly demonstrated that retinal microvascular abnormalities differ between lacunar and cortical stroke suggesting that a distinct small vessel vasculopathy may cause lacunar stroke. We have also identified MR markers of lacunar stroke. These results suggest that venular disease (a hitherto underresearched area) may play a role in the pathophysiology of lacunar stroke. Retinal microvascular abnormalities can act as markers for cerebral small vessel disease. We plan collaborative analyses with colleagues who have performed similar studies to further assess retinal abnormalities in lacunar stroke.

Lacunar stroke accounts for one quarter of all ischaemic stroke and in the long term carries a greater risk of death and disability than was previously realised. Much of our current knowledge originated from neuropathological studies in the 1950s and 1960s. In the last thirty years, brain computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionised our understanding of lacunar stroke and associated features of cerebral small vessel disease (SVD), namely white matter lesions (WML), enlarged perivascular spaces (EPVS) and brain microbleeds (BMB). The purpose of the projects which led to the writing of this thesis was to improve understanding of imaging characteristics of cerebral SVD. We aimed to assess (i) clinical and imaging features which might explain misclassification of lacunar infarcts as cortical infarcts and vice versa, (ii) the proportion of symptomatic lacunar infarcts progressing to lacunar cavities and associations of cavitation, (iii) completeness of reporting of lacunar lesions in the lacunar stroke literature, (iv) definitions and detection of lacunar lesions amongst SVD researchers, (v) the relationship between WML and carotid stenosis, (vi) clinical and imaging associations of EPVS and, (vii) observer variability in the assessment of EPVS and BMB, in order to develop visual rating scales. Section one describes neuroimaging of lacunar stroke. To investigate features which might explain clinical stroke subtype misclassification (‘clinical-imaging dissociation’), I used data from a stroke study. The main factor associated with clinical-imaging dissociation was diabetes, and in patients with acute lacunar infarction, proximity of the lacunar infarct to the cortex, age, diabetes and left hemisphere location. To investigate the proportion of symptomatic lacunar infarcts progressing to cavities, I used data from two stroke studies. A fifth of patients with acute lacunar ischaemic stroke showed definite cavitation on follow-up imaging at a median of 227 days; cavitation was associated with increasing time to follow-up. To assess completeness of reporting of lacunar lesions in the lacunar stroke literature, I reviewed 50 articles from three journals with a stroke focus. There was marked variation in terminology and descriptions of imaging definitions of lacunar lesions. To assess lacunar lesion definitions and detection amongst SVD researchers, I used an online survey consisting of case-based and non-case-based questions. There was marked variation in definitions and descriptions. Cavitated lesions were detected with the highest degree of confidence. Section two describes neuroimaging of associated features of cerebral SVD. Using data from two stroke studies, I examined the relationship between WML and ipsilateral carotid artery stenosis. There was no association between carotid stenosis and WML. I tested the association of EPVS with WML and lacunar stroke subtype using data from a stroke study. Total EPVS were associated with age and deep WML; basal ganglia (BG) EPVS were associated with age, centrum semiovale (CS) EPVS, cerebral atrophy and lacunar stroke subtype. Quantification of observer variability in EPVS rating was assessed on 60 MRI scans selected from a stroke study and an ageing cohort. Intrarater agreement was good and interrater agreement was moderate. Main reasons for interrater disagreement included the visualisation of very small EPVS and the presence of concomitant WML and lacunar lesions. Observer variability in BMB rating was quantified using MRI scans from a stroke study. Interrater agreement was moderate but improved following modification of the pilot rating scale (BOMBS; Brain Observer MicroBleed Scale), which had its main effect by differentiating ‘certain’ BMB from ‘uncertain’ BMB and BMB ‘mimics’. In conclusion, neuroimaging, particularly MRI, is a valuable tool for the investigation of lacunar stroke and associated features of cerebral SVD. With recent technological advances in both CT and MRI, neuroimaging will remain central to future SVD studies, hopefully leading to a much improved understanding of this important disease.

Lacunar strokes account for approximately a quarter of all ischaemic strokes and traditionally are thought to result from occlusion of a small deep perforating arteriole in the brain. Lacunar infarcts can be up to 2cm in diameter and are found in deep brain structures such as the thalamus and internal capsule. Despite their prevalence and specific accompanying clinical syndromes, the cause of lacunar stroke and its associated vascular pathology remain unclear. Many hypotheses as to the cause exist, which fall broadly into two categories; firstly, a direct occlusion via emboli or thrombus usually from a cardiac or large artery source, microatheroma (intrinsic lenticulostriate occlusion) or macroatheroma (parent artery occlusion) all operating primarily via ischaemia. Secondly, there could be an indirect occlusion resulting from vasospasm, endothelial dysfunction or other forms of endovascular damage (e.g. inflammation). Therefore the question of whether the resulting lesions are truly “ischaemic” or actually arise secondary to an alternative process is still under debate. To clarify the chain of pathological events ultimately resulting in lacunar stroke, in this thesis I firstly undertook a systematic assessment of human lacunar stroke pathology literature to determine the information currently available and the quality of these studies (including terminology). The majority of these studies were performed in patients who had died long after their stroke making it difficult to determine the early changes, and there were few patients with a clinically verified lacunar syndrome. Therefore I adopted alternative approaches. In this thesis, I systematically looked for all potential experimental models of lacunar stroke and identified what appears at present to be the most pertinent - the spontaneous pathology of the stroke-prone spontaneously hypertensive rat (SHRSP). However, the cerebral pathology described in this model to date is biased towards end stage pathology, with little information concerning the microvasculature (as opposed to the brain parenchyma) and confounding by use of salt to exacerbate pathology. Therefore, the aim of the experimental work in this thesis was to assess pathological changes within the cerebral vasculature and brain parenchyma of the SHRSP across a variety of ages (particularly young pre-hypertensive animals) and to look at the effects of salt loading on both the SHRSP and its parent strain (the Wistar Kyoto rat - WKY). Three related studies (qualitative and quantitative histology, immunohistochemistry and a microarray study of gene expression confirmed by quantitative PCR), revealed that the presence of inflammation (via significant changes in gene expression in the acute phase response pathway and increased immunostaining of activated microglia and astrocytes) plus alterations in vascular tone regulation, (via genetic alteration of the nitric oxide signaling pathway probably secondary to abnormal oxidative state), impaired structural integrity of the blood brain barrier (histological evidence of endothelial dysfunction and significantly decreased Claudin-5 staining) and reduced plasma oncotic potential (reduced albumin gene expression) are all present in the native SHRSP at 5 weeks of age, i.e. well before the onset of hypertension and without exposure to high levels of salt. We also confirmed previous findings of vessel remodelling at older ages likely as a secondary response to hypertension (thickened arteriolar smooth muscle, increased smooth muscle actin immunostaining). Furthermore, we found not only that salt exacerbated the changes see in the SHRSP at 21 weeks, but also that the control animals (WKY) exposed to a high salt intake developed features of cerebral microvascular pathology independently of hypertension (e.g. white matter vacuolation and significant changes in myelin basic protein expression). In conclusion, via the assessment of the most pertinent experimental model of lacunar stroke currently available, this thesis has provided two very important pieces of evidence: firstly that cerebral small vessel disease is primarily caused by a non-ischaemic mechanism and that any thrombotic vessel lesions occur as secondary end stage pathology; secondly that these features are not simply the consequence of exposure to raised blood pressure but occur secondary to abnormal endothelial integrity, inflammation, abnormal oxidative pathways influencing regulation of vascular tone and low plasma oncotic pressure. Patients with an innate susceptibility to increased blood brain barrier permeability and/or chronic inflammation could therefore have a higher risk of developing small vessel disease pathology and ultimately lacunar stroke and other features of small vessel disease. Research, addressing whether lacunar stroke patients should be treated differently to those with atherothromboembolic stroke is urgently needed.