Bakgrund: Intracerebral hjärnblödning (ICH) står för omkring 20 % av alla cerebrovaskulära sjukdomar och uppkommer oftast snabbt, vanligtvis i samband med aktivitet. Är blödningen stor kan hjärnans mittstrukturer flytta på sig, vilket i värsta fall kan leda till koma eller döden. Datortomografi (CT) och magnetisk resonanstomografi (MR) är idag de vanligaste radiologiska undersökningsmetoderna för att upptäcka en ICH.   Syfte: Att jämföra CT och MR vid diagnosticering av ICH, för att ta reda på respektive undersökningsmetods för- och nackdelar och därför kunna avgöra vilken metod som är att föredra vid diagnosticering av ICH.   Metod: En litteraturstudie baserad på artiklar funna i databasen PubMed genomfördes, där åtta artiklar hittades vid sökning. Två artiklar hittades vid en manuell sökning.   Resultat: MR är bra i ett tidigt stadium vid ICH. Gradient echos (GRE) roll vid MR verkar vara bra vid undersökning av ICH, men är likvärdig med CT, däremot tyder det på att GRE är mer noggrann än CT vad gäller mätning av blödningens volym, då den mätta volymen visar sig bli större med GRE än med CT däremot kan CT vara mindre tillförlitlig vid små ICH.   Konklusion: Denna litteraturstudies resultat tyder på att MR är en säkrare diagnostisk metod vid ICH än CT, däremot krävs större studier inom detta område för att kunna dra en definitiv slutsats.

Spontaneous (non-traumatic) intracerebral haemorrhage accounts for ~10% of all strokes in Western populations. Investigations may identify intracerebral haemorrhage (ICH) as ‘secondary’ to underlying causes such as tumours or aneurysms, but ~80% of ICHs which have no apparent underlying cause (so-called ‘primary’ ICH) tend to be attributed to small vessel vasculopathies such as arteriolosclerosis or cerebral amyloid angiopathy (CAA), on the basis of an adult’s risk factors and clinical and radiographic features of the ICH. The commonly accepted hypothesis is that CAA contributes to lobar ICH and arteriolosclerosis causes non-lobar ICH. In the following thesis, I set out to explore whether (a) the baseline demographic, clinical features and apolipoprotein E genotype of adults with lobar and non-lobar ICH differ, (b) the prognosis of adults with lobar and non-lobar ICH differ and (c) the neuroimaging correlates of small vessel disease in adults with lobar and non-lobar ICH differ since this might provide clues to the vasculopathies underlying lobar and non-lobar ICH. I explored (d) the strength of the association between CAA and ICH by systematically reviewing neuropathological case control studies and (e) the radiological and pathological features of lobar ICH to examine the nature of CAA in persons with lobar ICH and whether any computed tomography (CT) features of ICH are associated with CAA-related lobar ICH. I set up a prospective, community-based inception cohort study of adults with ICH in South East Scotland. Adults with spontaneous primary definite ICH had the opportunity to consent to participate in the Lothian Study of IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN), an ethically-approved, prospective community-based research study examining the causes of ICH using apolipoprotein E genotyping, brain MRI and research autopsy in case of death. Of 128 adults with first-ever spontaneous primary definite ICH diagnosed during 2010- 2011, age and pre-morbid hypertension did not differ by ICH location but a history of dementia was more common in adults with lobar ICH. The proportion of adults with one or more non-lobar brain microbleed (BMB) was significantly higher in adults with non-lobar ICH but I did not find any other differences in the severity or distribution of other neuroimaging correlates of small vessel disease between lobar and non-lobar ICH. The apolipoprotein e4 allele was more common in participants with lobar ICH in comparison to those with non-lobar ICH but the frequency of the e2 allele did not differ by ICH location. Adults with lobar ICH were significantly more likely to survive one year after their ICH in comparison to those with non-lobar ICH after adjustment for other known predictors of outcome. From a systematic review of neuropathological case control studies of CAA and ICH, stratified by ICH location, I found a significant association between CAA and lobar ICH but not with ICH in other locations. I examined the radiological and pathological features of 33 adults with first-ever lobar ICH. The presence of CAA or vasculopathy and the severity of CAA in a lobe affected by ICH was concordant with that of the corresponding contralateral unaffected lobe. Capillary CAA was associated with severe CAA. Subarachnoid extension of the ICH tended to be more frequent in those with CAA-related strictly lobar ICH. Having explored the incidence, risk factors and prognosis of lobar and non-lobar ICH, in future work I would aim to establish the strength of the association between CAA and ICH in different brain locations in a neuropathological case control study. Future work should examine the radiopathological features of lobar ICH in a larger cohort and the coexistence of other small vessel diseases, in particular arteriolosclerosis in persons with ICH.

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El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Background: Various randomized-controlled clinical trials (RCTs) have investigated the neuroprotective role of minocycline in acute ischemic stroke (AIS) or acute intracerebral hemorrhage (ICH) patients. We sought to consolidate and investigate the efficacy and safety of minocycline in patients with acute stroke. Methods: Literature search spanned through November 30, 2017 across major databases to identify all RCTs that reported following efficacy outcomes among acute stroke patients treated with minocycline vs. placebo: National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) scores. Additional safety, neuroimaging and biochemical endpoints were extracted. We pooled mean differences (MD) and risk ratios (RR) from RCTs using random-effects models. Results: We identified 7 RCTs comprising a total of 426 patients. Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs. In pooled analysis, minocycline demonstrated a favorable trend towards 3-month functional independence (mRS-scores of 0–2) (RR = 1.31; 95% CI 0.98–1.74, p = 0.06) and 3-month BI (MD = 6.92; 95% CI − 0.92, 14.75; p = 0.08). In AIS subgroup, minocycline was associated with higher rates of 3-month mRS-scores of 0–2 (RR = 1.59; 95% CI 1.19–2.12, p = 0.002; I2 = 58%) and 3-month BI (MD = 12.37; 95% CI 5.60, 19.14, p = 0.0003; I2 = 47%), whereas reduced the 3-month NIHSS (MD − 2.84; 95% CI − 5.55, − 0.13; p = 0.04; I2 = 86%). Minocycline administration was not associated with an increased risk of mortality, recurrent stroke, myocardial infarction and hemorrhagic conversion. Conclusions: Although data is limited, minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients. / Revisión por pares / Revisión por pares

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Intracerebral hemorrhage (ICH) is a devastating form of stroke that results from rupture of a blood vessel in the brain. Tissue inside the hematoma is irreversibly damaged soon after ICH onset and when this thesis research began, there was a dearth of information regarding pathological changes outside the hematoma. Inflammation is often proposed as a mechanism of injury, but very little information was available to show that inflammatory cells were in the right place at the right time to cause secondary brain injury. Using the collagenase-induced model of ICH, this work sought to better define spatial and temporal relationships between secondary brain injury and the inflammatory response after ICH. To test the hypothesis that reducing inflammation can protect the brain from secondary injury, minocycline, an antibiotic with established anti-inflammatory effects, was administered 6 hours after ICH onset. A small number of neurons die in the parenchyma bordering the hematoma between 6 hours and 3 days after ICH onset. This area was not associated with neutrophil infiltration, and most activated microglia/macrophages did not accumulate until after most neuron death had occurred. Despite a pronounced microglial response and prolonged increase in expression of many inflammatory genes, including complement receptor-3, interleukin-1 beta, interleukin-6, and interleukin-1 converting enzyme, no dying neurons were observed further outside the hematoma at any time. Interestingly, less early neuron death was observed in aged than in young animals, without a concomitant difference in the amount of tissue lost at 28 days. However, aged animals had less early microglial activation and a larger residual lesion, which might have resulted from impaired phagocytosis by activated microglia/macrophages. Minocycline was less effective in reducing microglial activation in aged animals, and did not reduce neuron death in either young or aged animals. Edema and BBB disruption was associated with degradation of the basal lamina protein, collagen type IV, and that damaged vessels are associated with tumor necrosis factor-alpha (TNFα)-positive neutrophils and active matrix metalloprotease-12 (MMP-12), all of which were reduced by delayed minocycline treatment. In contrast to ischemic stroke, there is a limited ‘penumbra’ outside the hematoma. Nevertheless, BBB damage in this region appears to be a potential target for protection. Furthermore, the prominent inflammatory response that continues for days after ICH does not appear to be associated with damage to other areas of the brain. Minocycline appears to protect the BBB by reducing neutrophil infiltration and the MMP-12 mediated basal lamina degradation. Future studies should investigate other targets for protection (i.e., white matter injury), and seek drugs that modulate the inflammatory response in aged animals and promote lesion resolution.

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Intracerebral hemorrhage (ICH) is a severe form of stroke, with a high mortality rate and often resulting in irreversible neurological deterioration. Although animal studies have provided insight into the etiology of the disease, many of the causative genes and mechanisms implicated in cerebral-vascular malformations are unknown. Treatment options remain ineffective. With the present models, the pathophysiological consequences of ICH can only be assessed in situ and after histological analysis. Furthermore, common deficiencies of the current models include the heterogeneity, low expression and low reproducibility of the desired phenotype. Hence, there is a requirement for novel approaches to model ICH pathogenesis. Zebrafish (Danio rerio) has gained recognition as a vertebrate model for stroke research. Through a combination of pharmacological blockers, metabolite rescue, genetic approaches, and confocal imaging analysis, I demonstrate a requirement for the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway in regulating developmental cerebral-vascular stabilization. A transient loss in HMGCR function induces ICH, characterised by progressive dilation of blood vessels, vascular permeability and vessel rupture. These effects are likely due to reduced prenylation of Rho GTPases, evidenced by morpholino-mediated blocking of the prenylation pathway and in vivo assessment of endothelial-specific localization of cdc42, a Rho GTPase family protein. These results are in conformity with recent clinical and experimental evidence. I have further shown that this model consistently replicates common pathoghysiological processes associated with ICH. The hemorrhages are associated with the disruption of the blood-brain barrier, vessel disintegration, hematoma expansion and edema into the adjacent brain regions. Also, enhanced apoptosis, activation of inflammatory mediators in the periphery of the hematoma, enriched heme oxygenase 1 (HO-1) expression and localised thrombosis were observed in these embryos. I show that the patterning and distribution of catecholaminergic neurons, response to sensory stimulus and swimming speed were impaired as a consequence of ICH. These results suggest that HMGCR contributes to cerebral-vascular stabilisation through Rho GTPase mediated-signalling and that zebrafish can serve as a powerful paradigm for the systemic analysis of the etiological and pathophysiological underpinnings of ICH and can help establish the basis for future studies into screening for putative therapeutics and elucidating mechanisms aiding functional recovery.

Intracerebral hemorrhage (ICH) results in secondary brain injury caused partially by blood and its metabolites. Survivors of ICH are often left with severe disabilities, therefore, decreasing the extent of this secondary injury may improve functional outcome of patients. Incubation of mouse brain slices with partially oxidized bilirubin, a neurotoxic blood breakdown product, caused a dose- and time-dependent decrease in axonal function, suggesting a reduced number of conducting myelinated axons. These effects did not occur when tissue was incubated with non-oxidized bilirubin. Injection of bilirubin into the corpus callosum of mice caused functional impairment of unmeylinated axons; however, immunohistochemical staining of the tissue showed evidence of structural damage to both oligodendrocytes and axons. This data provides evidence for functional and structural damage to white matter in the presence of partially oxidized bilirubin Therefore, diminishing the duration of presence of bilirubin and its oxidation in the brain warrants study as a means of decreasing secondary brain injury after ICH.