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This systematic review aimed to establish the range and quality of clinical and preclinical evidence supporting the association of individual microRNAs, and the use of microRNA expression in the diagnosis and prognosis of ischaemic or haemorrhagic stroke. Electronic databases were searched from 1993 to October 2021, using key words relevant to concepts of stroke and microRNA. Studies that met specific inclusion and exclusion criteria were selected for data extraction. To minimise erroneous associations, findings were restricted to microRNAs reported to change in more than two independent studies. Of the papers assessed, 155 papers reported a change in microRNA expression observed in more than two independent studies. In ischaemic studies, two microRNAs were consistently differentially expressed in clinical samples (miR-29b & miR-146a) and four were altered in preclinical samples (miR-137, miR-146a, miR-181b & miR-223-3p). Across clinical and preclinical haemorrhagic studies, four microRNAs were downregulated consistently (miR-26a, miR-126, miR-146a & miR-155). Across included studies, miR-126 and miR-146a were the only two microRNAs to be differentially expressed in clinical and preclinical cohorts following ischaemic or haemorrhagic stroke. Further studies, employing larger populations with consistent methodologies, are required to validate the true clinical value of circulating microRNAs as biomarkers of ischaemic and haemorrhagic stroke.

Introduction: Stroke is characterized by deleterious oxidative stress. Selenoprotein enzymes are essential endogenous antioxidants, and detailed insight into their role after stroke could define new therapeutic treatments. This systematic review aimed to elucidate how blood selenoprotein concentration and activity change in the acute phase of stroke. Methods: We searched PubMed, EMBASE, and Medline databases for studies measuring serial blood selenoprotein concentration or activity in acute stroke patients or in stroke patients compared to non-stroke controls. Meta-analyses of studies stratified by the type of stroke, blood compartment, and type of selenoprotein measurement were conducted. Results: Eighteen studies and data from 941 stroke patients and 708 non-stroke controls were included in this review. Glutathione peroxidase (GPx) was the only identified selenoprotein, and its activity was most frequently measured. Results from 12 studies and 693 patients showed that compared to non-stroke controls in acute ischaemic stroke patients, the GPx activity increased in haemolysate (standardized mean difference [SMD]: 0.27, 95% CI: 0.07–0.47) but decreased in plasma (mean difference [MD]: −1.08 U/L, 95% CI: −1.94 to −0.22) and serum (SMD: −0.54, 95% CI: −0.91 to −0.17). From 4 identified studies in 106 acute haemorrhagic stroke patients, the GPx activity decreased in haemolysate (SMD: −0.40, 95% CI: −0.68 to −0.13) and remained unchanged in plasma (MD: −0.10 U/L, 95% CI: −0.81 to 0.61) and serum (MD: −5.00 U/mL, 95% CI: −36.17 to 26.17) compared to non-stroke controls. Results from studies assessing the GPx activity in the haemolysate compartment were inconsistent and characterized by high heterogeneity. Conclusions: Our results suggest a reduction of the blood GPx activity in acute ischaemic stroke patients, a lack of evidence regarding a role for GPx in haemorrhagic stroke patients, and insufficient evidence for other selenoproteins.

/SummaryCerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology but this remains poorly characterized.To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients withCOL4A1/A2SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodelling and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cells tight junctions through paracrine actions.COL4A1/A2models also express high levels of matrix metalloproteinases (MMP) and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD.HighlightsA novel human iPSC-derived model of genetic SVD due to collagen IV (COL4A1/A2) mutations is describedMural cells expressingCOL4A1/A2mutations have prominent ECM abnormalities as seen in patients and mouse models and contribute to endothelial cells defectsECM and endothelial cells abnormalities can be rescued by MMP inhibition in theCOL4A1/A2model

Acute ischaemic and haemorrhagic stroke account for significant disability and morbidity burdens worldwide. The myeloid arm of the peripheral innate immune system is critical in the immunological response to acute ischaemic and haemorrhagic stroke. Neutrophils, monocytes, and dendritic cells (DC) contribute to the evolution of pathogenic local and systemic inflammation, whilst maintaining a critical role in ongoing immunity protecting against secondary infections. This review aims to summarise the key alterations to myeloid immunity in acute ischaemic stroke, intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH). By integrating clinical and preclinical research, we discover how myeloid immunity is affected across multiple organ systems including the brain, blood, bone marrow, spleen, and lung, and evaluate how these perturbations associate with real-world outcomes including infection. These findings are placed in the context of the rapidly developing field of human immunology, which offers a wealth of opportunity for further research.

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p

See Huuskonen et al. (doi:10.1093/brain/awab168) for a scientific commentary on this article. Systemic infection exacerbates Alzheimer’s disease. In this postmortem study, Asby et al. provide evidence that it does so by raising the levels of multiple cytokines in the brain and by exacerbating cerebral hypoperfusion and vascular leakage in Alzheimer’s disease, independently of the level of insoluble amyloid-β42., We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer’s disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer’s disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer’s disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer’s disease (Braak tangle stage V–VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III–IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in Alzheimer’s disease with systemic infection. Cerebral hypoperfusion—indicated by decreased MAG:PLP1 and increased vascular endothelial growth factor-A (VEGF)—and blood–brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in Alzheimer’s disease and vascular dementia patients, and also in non-dementia controls, with systemic infection. Amyloid-β42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of Alzheimer’s disease, and with infection (even in Braak stage 0–II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in Alzheimer’s disease; these were related to amyloid-β level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and blood–brain barrier leakiness associated with Alzheimer’s disease and vascular dementia, independently of the level of insoluble amyloid-β, and highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.

Multi-diffusion-time diffusion-weighted MRI can probe tissue microstructure, but the method has not been widely applied to the microvasculature. At long diffusion-times, blood flow in capillaries is in the diffusive regime, and signal attenuation is dependent on blood velocity ([Formula: see text]) and capillary segment length ([Formula: see text]). It is described by the pseudo-diffusion coefficient ([Formula: see text]) of intravoxel incoherent motion (IVIM). At shorter diffusion-times, blood flow is in the ballistic regime, and signal attenuation depends on [Formula: see text], and not [Formula: see text]. In theory, [Formula: see text] could be estimated using [Formula: see text] and [Formula: see text]. In this study, we compare the accuracy and repeatability of three approaches to estimating [Formula: see text], and therefore [Formula: see text]: the IVIM ballistic model, the velocity autocorrelation model, and the ballistic approximation to the velocity autocorrelation model. Twenty-nine rat datasets from two strains were acquired at 7 T, with [Formula: see text]-values between 0 and 1000 smm−2 and diffusion times between 11.6 and 50 ms. Five rats were scanned twice to assess scan-rescan repeatability. Measurements of [Formula: see text] were validated using corrosion casting and micro-CT imaging. The ballistic approximation of the velocity autocorrelation model had lowest bias relative to corrosion cast estimates of [Formula: see text], and had highest repeatability.

Stroke affects millions of people across the globe and infections following a stroke often lead to death or disability in patients. Looking rapidly after a stroke in patients, we identify early alterations to the innate and adaptive cells in circulation. Our findings highlight novel changes to dendritic cells, monocytes, haematopoietic stem and progenitor cells, B and T cells to be further investigated as they could have implications the development of post‐stroke infection and poorer patient outcomes., Summary Systemic immune changes following ischaemic stroke are associated with increased susceptibility to infection and poor patient outcome due to their role in exacerbating the ischaemic injury and long‐term disability. Alterations to the abundance or function of almost all components of the immune system post‐stroke have been identified, including lymphocytes, monocytes and granulocytes. However, subsequent infections have often confounded the identification of stroke‐specific effects. Global understanding of very early changes to systemic immunity is critical to identify immune targets to improve clinical outcome. To this end, we performed a small, prospective, observational study in stroke patients with immunophenotyping at a hyperacute time point (

The NLRP3 inflammasome is a multi-protein complex that regulates caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 release from innate immune cells in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4-octyl itaconate (4OI) and dimethyl fumarate (DMF), limit both expression and release of IL-1β following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses require further investigation. Using murine bone marrow-derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI, 4OI and DMF pre-treatment inhibit pro-inflammatory cytokine production in response to lipopolysaccharide (LPS), as well as inhibiting subsequent NLRP3 inflammasome activation induced by nigericin. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS-primed macrophages, mixed glia, OHSCs and human macrophages in response to nigericin and imiquimod, including ASC speck formation, caspase-1 activation, gasdermin D cleavage and IL-1β release. DMF, an approved treatment for multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism for DMF in multiple sclerosis through NLRP3 inhibition. The derivatives also reduced pro-IL-1α cleavage in response to the calcium ionophore ionomycin. Together, these findings reveal the immunometabolic regulation of both the priming and activation steps of NLRP3 activation in macrophages. Furthermore, we highlight itaconate and fumarate derivatives as potential therapeutic options in NLRP3- and IL-1α-driven diseases, including in the brain.

Introduction Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has highlighted the complex nature of the inflammatory microenvironment in these tumors. Methods A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic. Results The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo. Conclusion Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.

Anecdotal reports and clinical observations have recently emerged suggesting a relationship between COVID-19 disease and stroke, highlighting the possibility that infected individuals may be more susceptible to cerebrovascular events. In this review we draw on emerging studies of the current pandemic and data from earlier, viral epidemics, to describe possible mechanisms by which SARS-CoV-2 may influence the prevalence of stroke, with a focus on the thromboinflammatory pathways, which may be perturbed. Some of these potential mechanisms are not novel but are, in fact, long-standing hypotheses linking stroke with preceding infection that are yet to be confirmed. The current pandemic may present a renewed opportunity to better understand the relationship between infection and stroke and possible underlying mechanisms.

Apart from acute and chronic blood pressure lowering, we have no specific medications to prevent intracerebral haemorrhage (ICH) or improve outcomes once bleeding has occurred. One reason for this may be related to particular limitations associated with the current pre-clinical models of ICH, leading to a failure to translate into the clinic. It would seem that a breakdown in the ‘drug development pipeline’ currently exists for translational ICH research which needs to be urgently addressed. Here, we review the most commonly used pre-clinical models of ICH and discuss their advantages and disadvantages in the context of translational studies. We propose that to increase our chances of successfully identifying new therapeutics for ICH, a bi-directional, 2- or 3-pronged approach using more than one model species/system could be useful for confirming key pre-clinical observations. Furthermore, we highlight that post-mortem/ex-vivo ICH patient material is a precious and underused resource which could play an essential role in the verification of experimental results prior to consideration for further clinical investigation. Embracing multidisciplinary collaboration between pre-clinical and clinical ICH research groups will be essential to ensure the success of this type of approach in the future.

Post-stroke infection is a common complication of stroke that is associated with increased mortality and morbidity. We previously found that experimental stroke induces an ablation of multiple sub-populations of B cells and reduced levels of IgM antibody that coincide with the development of spontaneous bacterial pneumonia. Reduced circulating IgM concentrations were also observed in acute stroke patients. The loss of IgM antibody after stroke could be an important determinant of infection susceptibility and highlights this pathway as an important target for intervention.We treated mice with a low (replacement), dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after experimental stroke induced by middle cerebral artery occlusion (MCAO) or sham surgery, then recovered mice for 2 d or 5 d. The effect of treatment on lung bacterial burden, lung pathology, brain infarct volume, antibody levels and both lung and systemic cellular and cytokine immune profiles was determined. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved pathology but did not impact infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO, and treatment also reduced concentrations of pro-inflammatory cytokines in the lung. The effects of MCAO and IgM-IVIg treatment on the immune system were tissue specific as no impact on B cells or mouse immunoglobulins were found within the lung. However, the presence of human immunoglobulins from the IgM-IVIg treatment led to increased total lung immunoglobulin concentration. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced their capability to phagocytose Staphylococcus aureus bioparticles in vitro by increasing opsonisation.Low dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance phagocytic activity. Immunomodulatory effects of IgM-IVIg treatment, including reduced pro-inflammatory cytokine production, may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection.GRAPHICAL ABSTRACT

Summary Inflammasomes and the interleukin (IL)-1 family of cytokines are key mediators of both inflammation and immunothrombosis. Inflammasomes are responsible for the release of the pro-inflammatory cytokines IL-1β and IL-18, as well as releasing tissue factor (TF), a pivotal initiator of the extrinsic coagulation cascade. Uncontrolled production of inflammatory cytokines results in what is known as a “cytokine storm” leading to hyperinflammatory disease. Cytokine storms can complicate a variety of diseases and results in hypercytokinemia, coagulopathies, tissue damage, multiorgan failure, and death. Patients presenting with cytokine storm syndromes have a high mortality rate, driven in part by disseminated intravascular coagulation (DIC). While our knowledge on the factors propagating cytokine storms is increasing, how cytokine storm influences DIC remains unknown, and therefore treatments for diseases, where these aspects are a key feature are limited, with most targeting specific cytokines. Currently, no therapies target the immunothrombosis aspect of hyperinflammatory syndromes. Here we discuss how targeting the inflammasome and pyroptosis may be a novel therapeutic strategy for the treatment of hyperinflammation and its associated pathologies.

Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. [Methods] Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. [Results] Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (K [min]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. [Discussion] Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules., The authors acknowledge Lipoid Co. (Germany) for the lipid sample gifts, the staff at the bioimaging facility at the University of Manchester and NTU for advice on confocal imaging and data analysis. The authors also would like to acknowledge the access to the Leica Thunder Imager 3D Cell Culture system funded by the Office for Students at NTU. They also wish to thank the Biological Services Facility at the University of Manchester for the excellent animal husbandry. The cost of this study has been covered by: a) Dr Z Al-Ahmady research fellowship (School of Pharmacy and Optometry, University of Manchester), b) QR fund and Vice-Chancellor PhD studentship awarded for Dr Zahraa Al-Ahmady and Satinderdeep Kaur, Nottingham Trent University, c) BBSRC DTP Studentship awarded to Jessica Bates, Nottingham Trent University, d) MRC DTP studentship to Jack Barrington at University of Manchester. Jack Barrington also received support from the Natalie Kate Moss Trust, e) MRC grant (MR/N003586/1) for Eloise Lemarchand at University of Manchester, and f) EPSRC grant for Dr Ben Dickie at the University of Manchester (EP/S021510). Graphical abstract and schematic graphes were performed using Biorender.

As the COVID-19 pandemic moves towards endemic disease, it remains of key importance to identify groups of individuals vulnerable to severe infection and understand the biological factors that mediate this risk. Stroke patients are at increased risk of developing severe COVID-19, likely due to stroke-induced alterations to systemic immune function. Furthermore, immune responses associated with severe COVID-19 in patients without a history of stroke parallel many of the immune alterations induced by stroke, possibly resulting in a compounding effect that contributes to worsened disease severity. In this review, we discuss the changes to systemic immune function that likely contribute to augmented COVID-19 severity in patients with a history of stroke and the effects of COVID-19 on the immune system that may exacerbate these effects.

During recovery, stroke patients are at risk of developing long-term complications that impact quality of life, including changes in body weight and composition, depression and anxiety, as well as an increased risk of subsequent vascular events. The aetiologies and time-course of these post-stroke complications have not been extensively studied and are poorly understood. Therefore, we assessed long-term changes in body composition, metabolic markers and behaviour after middle cerebral artery occlusion in mice. These outcomes were also studied in the context of obesity, a common stroke co-morbidity proposed to protect against post-stroke weight loss in patients. We found that stroke induced long-term changes in body composition, characterised by a sustained loss of fat mass with a recovery of lean weight loss. These global changes in response to stroke were accompanied by an altered lipid profile (increased plasma free fatty acids and triglycerides) and increased adipokine release at 60 days. After stroke, the liver also showed histological changes indicative of liver damage and a decrease in plasma alanine aminotransferase (ALT) was observed. Stroke induced depression and anxiety-like behaviours in mice, illustrated by deficits in exploration, nest building and burrowing behaviours. When initial infarct volumes were matched between mice with and without comorbid obesity, these outcomes were not drastically altered. Overall, we found that stroke induced long-term changes in depressive/anxiety-like behaviours, and changes in plasma lipids, adipokines and the liver that may impact negatively on future vascular health. Electronic supplementary material The online version of this article (10.1007/s12975-019-00763-2) contains supplementary material, which is available to authorized users.

Modulation of peripheral immune cells in the spleen plays a key role in many life-threatening conditions such as stroke. Immune cell changes can lead to the excessive release of pro-inflammatory cytokines into the circulation and preferential loss of innate immune cells which can further exacerbate tissue damage and predispose patients to infectious complications. Reversing these processes represents an attractive treatment strategy and has shown to have beneficial effects in animal models of ischemic stroke, sepsis, traumatic brain injury (TBI) as well as myocardial infraction (MI). However, systemic interventions are often challenging to deliver due to the non-selective broad range of action of many treatments. More selective targeted treatment approaches are therefore desirable. The spleen is considered a natural filtration site for many nanomaterials due to the spontaneous tendency of this organ to filter blood-borne molecules. This selective targeting of nanomaterials to the spleen therefore offers considerable potential in the management of many conditions affected by peripheral inflammation. In this review, we will explore the key nanomaterials-related parameters that mediate splenic targeting and how these could influence the actual localization and function of nanomaterials once in the spleen. We aim to emphasize the potential of utilising nanomaterials as selective tools for peripheral immunomodulation to accelerate clinical translation.

Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and affects all levels of the brain’s vasculature. Features include diverse structural and functional changes affecting small arteries and capillaries that lead to a decline in cerebral perfusion. Due to an ageing population, incidence of cSVD is continually rising. Despite its prevalence and its ability to cause multiple debilitating illnesses, such as stroke and dementia, there are currently no therapeutic strategies for the treatment of cSVD. In the healthy brain, interactions between neuronal, vascular, and inflammatory cells are required for normal functioning. When these interactions are disturbed, chronic pathological inflammation can ensue. The interplay between cSVD and inflammation has attracted much recent interest, and this review discusses chronic cardiovascular diseases, particularly hypertension, and explores how the associated inflammation may impact on the structure and function of the small arteries of the brain in cSVD. Molecular approaches in animal studies are linked to clinical outcomes in patients, and novel hypotheses regarding inflammation and cSVD are proposed that will hopefully stimulate further discussion and study in this important area.

Stroke affects primarily aged and co-morbid people, aspects not properly considered to date. Since angiogenesis/vasculogenesis are key processes for stroke recovery, we purposed to determine how different co-morbidities affect the outcome and angiogenesis/vasculogenesis, using a rodent model of metabolic syndrome, and by dynamic enhanced-contrast imaging (DCE-MRI) to assess its non-invasive potential to determine these processes. Twenty/twenty-two month-old corpulent (JCR:LA-Cp/Cp), a model of metabolic syndrome and lean rats were used. After inducing the experimental ischemia by transient MCAO, angiogenesis was analyzed by histology, vasculogenesis by determination of endothelial progenitor cells in peripheral blood by flow cytometry and evaluating their pro-angiogenic properties in culture and the vascular function by DCE-MRI at 3, 7 and 28 days after tMCAO. Our results show an increased infarct volume, BBB damage and an impaired outcome in corpulent rats compared with their lean counterparts. Corpulent rats also displayed worse post-stroke angiogenesis/vasculogenesis, outcome that translated in an impaired vascular function determined by DCE-MRI. These data confirm that outcome and angiogenesis/vasculogenesis induced by stroke in old rats are negatively affected by the co-morbidities present in the corpulent genotype and also that DCE-MRI might be a technique useful for the non-invasive evaluation of vascular function and angiogenesis processes.

Advances in our understanding of ADAMTS13 structure, and the conformation changes required for full activity, have rejuvenated the possibility of its use as a thrombolytic therapy. We have tested a novel Ala1144Val ADAMTS13 variant (constitutively active [ca] ADAMTS13) that exhibits constitutive activity, characterized using in vitro assays of ADAMTS13 activity, and greatly enhanced thrombolytic activity in 2 murine models of ischemic stroke, the distal FeCl3 middle cerebral artery occlusion (MCAo) model and transient middle cerebral artery occlusion (tMCAO) with systemic inflammation and ischemia/reperfusion injury. The primary measure of efficacy in both models was restoration of regional cerebral blood flow (rCBF) to the MCA territory, which was determined using laser speckle contrast imaging. The caADAMTS13 variant exhibited a constitutively active conformation and a fivefold enhanced activity against fluorescence resonance energy transfer substrate von Willebrand factor 73 (FRETS-VWF73) compared with wild-type (wt) ADAMTS13. Moreover, caADAMTS13 inhibited VWF-mediated platelet capture at subphysiological concentrations and enhanced t-PA/plasmin lysis of fibrin(ogen), neither of which were observed with wtADAMTS13. Significant restoration of rCBF and reduced lesion volume was observed in animals treated with caADAMTS13. When administered 1 hour after FeCl3 MCAo, the caADAMTS13 variant significantly reduced residual VWF and fibrin deposits in the MCA, platelet aggregate formation, and neutrophil recruitment. When administered 4 hours after reperfusion in the tMCAo model, the caADAMTS13 variant induced a significant dissolution of platelet aggregates and a reduction in the resulting tissue hypoperfusion. The caADAMTS13 variant represents a potentially viable therapeutic option for the treatment of acute ischemic stroke, among other thrombotic indications, due to its enhanced in vitro and in vivo activities that result from its constitutively active conformation.

International audience; In this review we discuss the possibility that the phenomenon of microglial priming can be explained by the mechanisms that underlie trained immunity. The latter involves the enhancement of inflammatory responses by epigenetic mechanisms that are mobilized after first exposure to an inflammatory stimulus. These mechanisms include long-lasting histone modifications, including H3K4me1 deposition at latent enhancer regions. Although such changes may be beneficial in peripheral infectious disease, in the context of microglial priming they may drive increased microglia reactivity that is damaging in diseases of brain aging.

Background Stroke is a major cause of disability and mortality. Poorer outcome after stroke is associated with concomitant inflammatory and infectious disease. Periodontitis is a chronic inflammatory disease of the dental supporting structures and is a prominent risk factor for many systemic disorders, including cardiovascular disease and stroke. While epidemiological studies suggest that periodontitis increases the likelihood of stroke, its impact on stroke severity is poorly understood. Here, we sought to determine the contribution of periodontitis to acute stroke pathology. Methods We characterized a murine ligature model of periodontitis for inflammatory responses that could potentially impact stroke outcome. We applied this model and then subjected mice to either transient or permanent middle cerebral artery occlusion. We also enhanced the periodontitis model with repeated intravenous administration of a periodontal-specific lipopolysaccharide to better mimic the clinical condition. Results Ligature-induced periodontitis caused bone loss, bacterial growth, and increased local inflammatory cell trafficking. Systemically, periodontitis increased circulating levels of pro-inflammatory cytokines, and primed bone marrow monocytes to produce elevated tumour necrosis factor-alpha (TNFα). Despite these changes, periodontitis alone or in tandem with repeated lipopolysaccharide challenge did not alter infarct volume, blood–brain barrier breakdown, or systemic inflammation after experimental stroke. Conclusions Our data show that despite elevated systemic inflammation in periodontitis, oral inflammatory disease does not impact acute stroke pathology in terms of severity, determined primarily by infarct volume. This indicates that, at least in this experimental paradigm, periodontitis alone does not alter acute outcome after cerebral ischemia.

The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.

Intracerebral hemorrhage is a devastating global health burden with limited treatment options and is responsible for 49% of 6.5 million annual stroke-related deaths comparable to ischemic stroke. Despite the impact of intracerebral hemorrhage, there are currently no effective treatments and so weaknesses in the translational pipeline must be addressed. There have been many preclinical studies in intracerebral hemorrhage models with positive outcomes for potential therapies in vivo, but beyond advancing the understanding of intracerebral hemorrhage pathology, there has been no translation toward successful clinical application. Multidisciplinary preclinical research, use of multiple models, and validation in human tissue are essential for effective translation. Repurposing of therapeutics for intracerebral hemorrhage may be the most promising strategy to help relieve the global health burden of intracerebral hemorrhage. Here, we have reviewed the existing literature to highlight repurposable drugs with successful outcomes in preclinical models of intracerebral hemorrhage that have realistic potential for development into the clinic for intracerebral hemorrhage.

Assessment of outcome in preclinical studies of vascular cognitive impairment (VCI) is heterogenous. Through an ARUK Scottish Network supported questionnaire and workshop (mostly UK-based researchers), we aimed to determine underlying variability and what could be implemented to overcome identified challenges. Twelve UK VCI research centres were identified and invited to complete a questionnaire and attend a one-day workshop. Questionnaire responses demonstrated agreement that outcome assessments in VCI preclinical research vary by group and even those common across groups, may be performed differently. From the workshop, six themes were discussed: issues with preclinical models, reasons for choosing functional assessments, issues in interpretation of functional assessments, describing and reporting functional outcome assessments, sharing resources and expertise, and standardization of outcomes. Eight consensus points emerged demonstrating broadly that the chosen assessment should reflect the deficit being measured, and therefore that one assessment does not suit all models; guidance/standardisation on recording VCI outcome reporting is needed and that uniformity would be aided by a platform to share expertise, material, protocols and procedures thus reducing heterogeneity and so increasing potential for collaboration, comparison and replication. As a result of the workshop, UK wide consensus statements were agreed and future priorities for preclinical research identified.