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pathogenesis

Regulatory T Cells in Females Provide Endogenous Neuroprotection, But Increase Secondary Neurodegeneration in Males in Neonatal Encephalopathy in Mice

Kristina Shkirkova, BSc

Beckmann L, Obst S, Labusek N, Abberger H, Köster C, Klein-Hitpass L, Schumann S, Kleinschnitz C, Hermann DM, Felderhoff-Müser U, et al. Regulatory T Cells Contribute to Sexual Dimorphism in Neonatal Hypoxic-Ischemic Brain Injury. Stroke. 2022.

Regulatory T cells (Tregs) are specialized T cells that have an ability to suppress immune response. Recent evidence suggests a sexual dimorphism in the role Tregs play after brain injury.

In the study recently published in Stroke by Beckmann et al., experimental administration of hypoxia-ischemia to neonatal mice by ligation of the right common carotid artery, as a model of neonatal encephalopathy, resulted in increased cerebral Tregs infiltration into the brain. Flow cytometry revealed that females experienced significantly higher frequency and total amount of Treg infiltration than males 24 hours after the induced hypoxia-ischemia in the brain but not in the peripheral tissue. To further investigate the functional contribution of Tegs in both sexes, a special agent, DTX, was used to deplete the number of Tregs in mice. As a result of Treg depletion, a more significant injury was observed in female cortex and hippocampus, while in males, the injury was decreased in these areas. Depletion of Tregs also resulted in functional deficits only in females in early forelimb coordination test as well as long-term exploratory activity. In the hippocampus, Treg depletion increased microglial response, endothelial activation, and leukocyte accumulation in female compared to non-depleted females. Females were also observed to have increased basil lamina disruption following Treg depletion, while for males, Treg depletion provided vascular protection. These differences between sexes were not explained by levels of female hormone estradiol, as there was not a difference observed in serum estradiol levels between males and females. Independent of sex hormones, female Tregs were immunosuppressive on effector T cell compared with male, with Myc Targets, mTORC1 signaling and oxidative phosphorylation pathways showing prominence in gene set enrichment analysis.

By |February 4th, 2022|basic sciences, pathogenesis|Comments Off on Regulatory T Cells in Females Provide Endogenous Neuroprotection, But Increase Secondary Neurodegeneration in Males in Neonatal Encephalopathy in Mice
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ESOC 2021: Thrombosis and Inflammation Team Up in Ischemic Stroke

Aurora Semerano, MD
@semerano_aurora

European Stroke Organisation Conference
September 1–3, 2021

Session: “Inflammation, Thrombosis and Stroke Pathogenesis,” September 3, 2021

The complex interplay between inflammation and thrombosis in ischemic stroke was the subject of the interesting scientific session chaired by Mervyn D. Vergouwen (Netherlands) and Christoph Kleinschnitz (Germany). The five speakers dissected the topic by presenting the main players involved in pathophysiology of stroke-related thrombo-inflammation, and prospected potential interventions of immune modulation.

Bernhard Nieswandt (Germany) showed how platelets, besides their well-established functions, have a critical role in inflammation. They are involved not only in the process of thrombus formation, but also in the subsequent mechanisms of infarct growth. Identifying the optimal target to interfere with platelet activity is crucial, due to the possible risk of hemorrhagic transformation. Two promising axes are discussed, namely the immunomodulatory function of von Willebrand Factor through its receptor on platelets Glycoprotein Ib, and the interplay with the kallikrein system and Factor XII activation. The resulting infiltration of immune cells (including T cells) into the ischemic brain contributes to the damage. Importantly, he pointed out that thrombo-inflammation doesn’t start after recanalization, but it is still ongoing during the occlusion, sustained by the collateral blood flow. This is supported in humans by a recent elegant work,1 which reported for the first time that leukocytes strongly accumulate in cerebral vessels distal to the occlusion. Bearing this in mind is fundamental to designing the optimal treatment.

By |September 20th, 2021|clinical, Conference, pathogenesis|Comments Off on ESOC 2021: Thrombosis and Inflammation Team Up in Ischemic Stroke
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Author Interview: Dr. Masafumi Ihara on “Oral Carriage of Streptococcus mutans Harboring the cnm Gene Relates to an Increased Incidence of Cerebral Microbleeds”

Dr. Masafumi Ihara, left, and Dr. Saurav Das

An  interview with Dr. Masafumi Ihara, MD, PhD; Head, Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan.

Interviewed by Dr. Saurav Das, MD; Fellow in Vascular Neurology, Washington University School of Medicine, St. Louis.

They will be discussing the article “Oral Carriage of Streptococcus mutans Harboring the cnm Gene Relates to an Increased Incidence of Cerebral Microbleeds,” published in the December 2020 issue of Stroke.

Dr. Das: Dr. Ihara, on behalf of the Blogging Stroke team, it is my pleasure to welcome you to this author interview about your publication in Stroke regarding the association between CNM gene-positive Streptococcus mutans and increased incidence of cerebral microbleeds. Given Streptococcus mutans is a common pathogen associated with dental caries, it is a potential treatment target to prevent increase in cerebral microbleeds.

Many of our readers come from a stroke background and may not be as familiar with oral pathology. It will be of interest to start by discussing some common oral pathogens implicated in cerebrovascular disease. Also, what is specific about Streptococcus mutans, and particularly the ones positive for CNM gene?

Dr. Ihara: More than 500 bacterial species have been estimated to exist in the oral cavity, and many remain to be identified and characterized. Of all the known pathogenic oral bacteria, a few have been linked to cerebrovascular diseases. Our co-investigator Prof. Nakano reported that certain strains of Streptococcus mutans (S. mutans) are potential risk factors for intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats and mice with photochemically induced middle cerebral artery occlusion.1 This corresponds with findings showing periodontal infections to be risk factors for stroke, and that S. mutans is detected in 100% of samples of atherosclerotic plaques. S. mutans is a major pathogen in dental caries that can cause bacteremia by dental procedures, such as tooth extraction and periodontal surgery, or even tooth brushing in daily life. S. mutans is well known to be responsible for infective endocarditis. The hemorrhage-causing S. mutans strains express collagen-binding protein Cnm on their cell surface, enabling them to attach to exposed collagen fibers on the surface of damaged blood vessels and prevent platelet activation, thereby, leading to hemorrhages. Another dental bacterium, Porphyromonas gingivalis (P. gingivalis), is also found in atherosclerotic plaques and has been linked to the increased risk of ischemic stroke. P. gingivalis adheres to and infects endothelial cells not only to increase the expression of endothelial adhesion molecules and promote monocyte/macrophage infiltration, but also to produce cysteine proteinase gingipains, which activate protease-activated receptors-1 and -4 on platelets to induce platelet aggregation. Thus, infection from P. gingivalis could cause small vessel disease pathology through thrombotic occlusion and BBB disruption through inflammation.

By |December 7th, 2020|author interview, clinical, pathogenesis|Comments Off on Author Interview: Dr. Masafumi Ihara on “Oral Carriage of Streptococcus mutans Harboring the cnm Gene Relates to an Increased Incidence of Cerebral Microbleeds”
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Machine Learning as a Tool for Etiological Investigation in Stroke Medicine

Aurora Semerano, MD
@semerano_aurora

Kamel H, Navi BB, Parikh NS, Merkler AE, Okin PM, Devereux RB, Weinsaft JW, Kim J, Cheung JW, Kim LK, et al. Machine Learning Prediction of Stroke Mechanism in Embolic Strokes of Undetermined Source. Stroke. 2020;51:e203–e210.

In 2014, when the concept of embolic stroke of undetermined source (ESUS) was proposed,1 confidence existed that ESUS could represent a single entity which would have benefitted from a unified treatment. However, after two randomized clinical trials did not show benefit of direct oral anticoagulation for secondary prevention of ESUS patients,2,3 it is now common opinion that these patients rather represent a heterogeneous population and are likely to benefit from tailored, personalized therapies. Today, ESUS represents a useful definition to identify patients deserving extended diagnostic workup, while prevention therapy for these patients remains elusive, and clinical stroke recurrence is still an issue. Both subgroup analyses from the above-mentioned clinical trials and new research studies have been developed or are ongoing, to better understand the pathophysiology of ESUS and help in patient selection.

In such a phenotypically heterogeneous population, one big effort is to identify patient subsets with a single or group of underlying mechanisms likely to respond to an established treatment. With this right purpose of uncover the “hidden structure” in a complex scenario, the recent study from Kamel et al.4 employs a machine learning approach. Firstly, a supervised machine-learning algorithm was developed to distinguish cardioembolic versus non-cardioembolic strokes in a population of 1083 patients with known stroke etiology, by entering data about demographics, comorbidities, vitals, laboratory results, and echocardiograms. After the learning process, the system finally resulted to distinguish cardioembolic from non-cardioembolic strokes with excellent accuracy (area under the curve, AUC=0.85).

By |October 12th, 2020|clinical, pathogenesis|Comments Off on Machine Learning as a Tool for Etiological Investigation in Stroke Medicine
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Article Commentary: “Nonfocal Transient Neurological Attacks Are Associated With Cerebral Small Vessel Disease”

Richard Jackson, MD

Oudeman EA, Greving JP, Van den Berg-Vos RM, Biessels GJ, Bron EE, van Oustenbrugge R, et al. Nonfocal Transient Neurological Attacks Are Associated With Cerebral Small Vessel Disease. Stroke. 2019;50:3540–3544.

Oudeman et al. have published a paper on non-focal TIA’s which have been called transient neurological attacks (TNAs). As neurologists, we are always trained to localize first, but anyone who has taken stroke calls from the ER knows that not all the presentations and calls are localizable, such as those mentioned in this paper and described as “bilateral weakness, unsteadiness, or confusion.” In the introduction, the authors mention that these were historically thought to be secondary to hypoperfusion, but recent imaging have shown them to be associated with ischemia. Underlying risk factors are common to traditional TIA’s, such as smoking and hypertension, but not atherosclerotic disease or atrial fibrillation, which led to the current investigation for an association between small vessel disease and TNAs.

By |March 16th, 2020|clinical, pathogenesis|Comments Off on Article Commentary: “Nonfocal Transient Neurological Attacks Are Associated With Cerebral Small Vessel Disease”
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Effect of HRV on the Association Between Obstructive Sleep Apnea and Small Vessel Disease

Kristina Shkirkova, BSc
@KShkirkova

Del Brutto OH, Mera RM, Costa AF, Castillo PR. Effect of Heart Rate Variability on the Association Between the Apnea-Hypopnea Index and Cerebral Small Vessel Disease. Stroke. 2019;50:2486–2491.

Obstructive Sleep Apnea (OSA) is a form of sleep-disordered breathing that has been increasingly implicated in the pathogenesis of cerebral small vessel disease (cSVD). OSA is associated with recurrent episodes of hypoxia, altered cerebral autoregulation, and sympathetic overactivity, which may be contributing triggers for pathophysiology of cSVD. A recent study by Del Brutto et al. used nighttime Heart Rate Variability (HRV) as a measure of sympathetic upregulation to study the association between OSA and cSVD. HRV measures variation in the intervals between heartbeats and is used as a reflection of the balance between sympathetic and parasympathetic tone. Apnea-Hypopnea Index was used to access the degree of OSA and the total cSVD score was chosen to quantify cSVD burden. The study used data from the Atahualpa Project, which included elderly (age above 60) residents of the Atahualpa rural village on the coast of Ecuador. A total of 176 participants who underwent clinical assessment, magnetic resonance imaging (MRI), single-night polysomnography, and 24-hour Holter monitoring were selected for the analysis.

Among study participants, the mean age was 71.8, and 64% were women. The univariate analysis showed that daytime HRV below the 50th percentile was associated with female gender and lower mean percentage of O2 saturation. The nighttime HRV below the 50th percentile was associated with body mass index (BMI) higher than 30 kg/m2. In the generalized linear model analysis, with and without confounding variables, there was a significant association between the cSVD score and AHI (p=0.026). Furthermore, a negative association was observed between sCVD and nighttime HRV, but not daytime HRV (p=0.001). Interaction model analysis showed a significant interaction of nighttime HRV on the relationship between AHI and the cSVD score (P=0.001). The total effect between AHI and the cSVD score mediated by HRV was 30.8%. Additionally, contour plots showed the effect of nighttime HRV on the association between AHI and the cSVD score.

By |November 5th, 2019|clinical, pathogenesis|Comments Off on Effect of HRV on the Association Between Obstructive Sleep Apnea and Small Vessel Disease
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Clot Histology: A Possible Clue to the Etiology of Ischemic Stroke

Piyush Ojha, MBBS, MD, DM

Fitzgerald S, Dai D, Wang S, Douglas A, Kadirvel R, Layton KF, et al. Platelet-Rich Emboli in Cerebral Large Vessel Occlusion Are Associated With a Large Artery Atherosclerosis Source. Stroke. 2019;50:1907–1910.

Stroke accounts for approximately 10% of all deaths worldwide and leads to substantial long-term disability. The majority of the strokes are ischemic in origin. No identifiable cause is found in up to one-third of the patients after a standard evaluation, which limits the options for secondary stroke prevention. Mechanical thrombectomy has been found to be highly effective in patients with large vessel occlusions (LVO). In addition to the revascularisation, endovascular procedures have also created a unique opportunity to identify the likely stroke pathogenesis by providing thrombus material for further study. Emerging insights on various thrombus characteristics can not only provide valuable information that might be useful for guiding acute therapies, but also in optimizing secondary stroke prevention, as different components in the clot may respond to different pharmacological strategies.

Studies have tried to correlate thrombus histological composition and stroke pathogenesis. Sporns et al.1 observed that clots from a cardioembolic source had a higher proportion of fibrin/platelets and fewer red blood cells than noncardioembolic thrombi.

By |August 30th, 2019|clinical, pathogenesis|Comments Off on Clot Histology: A Possible Clue to the Etiology of Ischemic Stroke
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Atrial Thromboembolism: Looking Beyond Atrial Fibrillation

Andrea Morotti, MD

Kamel H, Bartz TM, Elkind MSV, Okin PM, Thacker EL, Patton KK, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke. 2018

Many patients experiencing cryptogenic stroke with an embolic pattern lack a documented source of thromboembolism, even after an extensive diagnostic workup and prolonged follow-up. In particular, atrial fibrillation (AF) is detected in less than half of these patients. Increasing evidence suggested that atrial dysfunction may lead to thromboembolism independently of AF. In this large, multicenter prospective study, Dr. Kamel and colleagues explored the association between markers of atrial cardiopathy and the risk of incident ischemic stroke.

By |April 6th, 2018|clinical, pathogenesis|Comments Off on Atrial Thromboembolism: Looking Beyond Atrial Fibrillation
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Resistant Atherosclerosis

Philip Chang, MD

Spence JD, Solo K. Resistant Atherosclerosis: The Need for Monitoring of Plaque Burden. Stroke. 2017

In this study, Spence and Solo demonstrated that measurement of LDL-C levels is likely inadequate to assess a patient’s response to statin therapy. In their database of 4512 patients with 2 measurements of LDL-C and 2 carotid duplex scans measuring total plaque area, they found that neither LDL-C levels nor change in LDL-C levels predicted carotid artery plaque burden or progression of plaque area. Interestingly, they found that in the 6% of patients with low LDL-C levels (<38mg/dL), almost half experienced progression of their plaque burden. In addition, they found that it was not uncommon for patients with LDL-C levels of over 70mg/dL to experience plaque regression. This suggests that merely relying on an LDL-C level to predict plaque burden is insufficient.

By |July 17th, 2017|clinical, pathogenesis|Comments Off on Resistant Atherosclerosis
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Cortical Neuronal Damage in Atherosclerotic Large Artery Disease

Russell Mitesh Cerejo, MD

Yamauchi H, Kagawa S, Kishibe Y, Takahashi M, Higashi T. Progressive Cortical Neuronal Damage and Chronic Hemodynamic Impairment in Atherosclerotic Major Cerebral Artery Disease. Stroke. 2016

In their paper, the authors set out to determine whether selective cortical neuronal damage manifests as a decrease in BZRs in the normal appearing cerebral cortex of patients with atherosclerotic ICA or MCA occlusive disease, and furthermore whether these changes can be correlated with chronic hemodynamic impairment at baseline or hemodynamic deterioration. They studied 80 patients with atherosclerotic ICA or MCA disease with 17 having TIAs, and 38 having completed stroke.

The authors found that the BZR index in 40 patients was increased during follow-up (mean 26±20 months). In multivariable logistic regression analyses, increases in the BZR index were associated with the decreased cerebral blood flow at baseline and an increased oxygen extraction fraction during follow-up. They hypothesize that misery perfusion at baseline is associated with subsequent development of ischemic cortical neuronal damage. The contribution of the increased BZR index at baseline suggests that patients with misery perfusion have already suffered some ischemic cortical neuronal damage and may be at particular risk for progressive cortical neuronal damage.
They also found that increases in the oxygen extraction fraction during follow-up were associated with a lack of statin use. They suggest that revascularization procedures can improve hemodynamic impairment and thus may be beneficial to patients vulnerable to selective neuronal damage. 


By |June 6th, 2016|pathogenesis|Comments Off on Cortical Neuronal Damage in Atherosclerotic Large Artery Disease
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