Hyperthermia worsens outcome after ischemia. While it seems reasonable that hyperthermia would also worsen outcome after intracerebral hemorrhage (ICH), clinical studies attempting to find a causative relationship between hyperthermia and outcome have been inconclusive. We induced ICH with an injection of autologous whole blood (100 l) immediately followed by 3 hours of hyperthermia (HYPER; 39C) or normothermia (NORMO; 37C). Surprisingly, hyperthermia reduced edema at 72 hours, and improved outcome on day 3 post-ICH. There were no behavioural differences at later time points (day 11 and 32 post-ICH) and no difference in lesion volume (NORMO 14.0 mm3, HYPER: 14.5 mm3). Overall, this study does not support the hypothesis that mild, transient hyperthermia worsens outcome after ICH. Further research is needed to determine if more severe or prolonged hyperthermia worsens outcome, or if the cause of hyperthermia (e.g. infection) is important.

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.

abstract: Intracerebral hemorrhage (ICH) is a devastating type of acute brain injury with high mortality and disability. Acute brain injury swiftly alters the immune reactivity within and outside the brain; however, the mechanisms and influence on neurological outcome remains largely unknown. My dissertation investigated how ICH triggers focal and systemic immune responses and their impact hemorrhagic brain injury. At the focal level, a significant upregulation of interleukin (IL)-15 was identified in astrocytes of brain sections from ICH patients. A transgenic mouse line where the astrocytic IL-15 expression is controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15tg) was generated to investigate its role in ICH. Astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. Aggravated ICH injury was accompanied by an accumulation of pro-inflammatory microglia proximal to astrocytes in perihematomal tissues, microglial depletion attenuated the augmented ICH injury in GFAP-IL-15tg mice. These findings suggest that IL-15 mediates the crosstalk between astrocytes and microglia, which worsens ICH injury.Systemic immune response was investigated by leveraging the novel method of obtaining and analyzing bone marrow cells from the cranial bone flaps of ICH patients. A swift increase of hematopoietic stem cell (HSCs) population in the bone marrow was identified, along with a shift towards the myeloid cell lineage. Human findings were mirrored in an ICH mouse model. Fate mapping these HSCs revealed increased genesis of Ly6Clow monocytes in the bone marrow, which transmigrate into the hemorrhagic brain and give rise to alternative activation marker bearing macrophage. Blockade of the β3-adrenergic receptor or inhibition of Cdc42 abolished ICH-induced myeloid bias of HSCs. Importantly, mirabegron, a Food and Drug Administration-approved β3 adrenergic receptor agonist, and a Cdc42 activator, IL-3, enhanced bone marrow generation of Ly6Clow monocytes and improved recovery. These results suggest that brain injury modulates HSC lineage destination to curb distal brain inflammation, implicating the bone marrow as a unique niche for self-protective neuroimmune interactions. Together, these results demonstrate how acute brain injury exerts a profound yet distinct effect on immune responses within and outside the brain and sheds new light on neuroimmune interactions with potential clinical implications. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2020

Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis. It is a diagnosis of exclusion and often diagnosed post mortem on pathologic evaluation. Cerebral angiography can be suggestive, but biopsy is required. Symptoms can vary from headache to focal cranial nerve deficits. On the more severe spectrum, patients can present with ischemic and vary rarely hemorrhagic stroke. We present in this case report key clinical pearls regarding suspected diagnosis. Younger patients with cortical hemorrhages may have PACNS instead of the more common cerebral amyloid angiopathy. Early suspicion may aid in initiating effective treatment as we highlight in the discussion.

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Role of blood biomarkers in spontaneous intracerebral hemorrhage Background: The study of blood biomarkers can offer new possibilities in diagnostics, prognostication, determination of etiology, and management of spontaneous intracerebral hemorrhage. The aim of our study was to assess the relationship between a panel of selected blood biomarkers and clinical and radiodiagnostic parameters in patients with spontaneous intracerebral hemorrhage. Primarily, the aim was to find a prognostic biomarker which could help in deciding on the optimal categorization of treatment. Patients and methods: A total of 70 patients were prospectively included in this study. The following blood biomarkers were determined: glial fibrillary acidic protein, S100B protein, matrix metalloproteinase 9, interleukin 6, interleukin 10, 25-hydroxyvitamin D, 1,25- dihydroxyvitamin D, total cholesterol, leukocyte counts, blood glucose and C-reactive protein. These were then correlated with selected clinical and radiodiagnostic parameters. Results: Relative to hematoma volume a statistically significant positive correlation was found for S100B, interleukin 10, interleukin 6 and blood glucose (S100B: ρ= 0,54, p< 0,001, IL-10: ρ= 0,43, p< 0,001, IL-6: ρ= 0,26, p= 0,027, blood glucose: ρ= 0,24, p= 0,045). Using multivariate analysis, a...

Purpose: Traumatic brain injury (TBI) leads to important and deleterious neuroinflammation, as evidenced by edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. Strategies that block inflammatory and oxidative mediators have been shown to induce neuroprotective and anti-inflammatory effects after brain injury. After TBI, cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation. In this study, we hypothesized that cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation after TBI and, in conjunction with leukocytes, represent a key cellular target for statin therapy. We investigated the effect of acute and continuous treatment of simvastatin on behavior and inflammation in adult rats following experimental TBI. Materials and Methods: Cortical contusions were induced using a device adapted from the impact method. There were 3 groups: (1) sham group, craniotomy only; (2) control group, TBI without treatment; and (3) treatment group, TBI with simvastatin administration. The treatment group received 15 mg/kg of simvastatin daily for 3 days. Neurological function was assessed with the grip test (Grip strength meter, Singa). Results: Non-treatment control group had a significantly greater increase in ICAM-1 expression from pre-injury to the post-injury 72 h time point, compared to the simvastatin treatment group. The treatment group had a significantly smaller amount of reduction in successful trials in grip test than the control group did from baseline to 72 h. The analysis of western blot and pathological study also demonstrated similar results. Conclusion: Our findings indicate that continuous administration of simvastatin after injury attenuates the cerebral vascular endothelial inflammatory response and improves functional and histological outcomes in a rat model of TBI. This improvement is associated with a reduction in expression of ICAM-1 in the blood and brain after rat TBI when compared with the untreated control group. Hence, we recommend simvastatin administration in the first 72 h following TBI.

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<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. / 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<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.