Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology.

To better define roles that astrocytes and microglia play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

Unexplored Roles of Erythrocytes in Atherothrombotic Stroke.

Stroke constitutes the second highest cause of morbidity and mortality worldwide while also impacting the world economy, triggering substantial financial burden in national health systems. High levels of blood glucose, homocysteine, and cholesterol are causative factors for atherothrombosis. These molecules induce erythrocyte dysfunction, which can culminate in atherosclerosis, thrombosis, thrombus stabilization, and post-stroke hypoxia. Glucose, toxic lipids, and homocysteine result in erythrocyte oxidative stress. This leads to phosphatidylserine exposure, promoting phagocytosis. Phagocytosis by endothelial cells, intraplaque macrophages, and vascular smooth muscle cells contribute to the expansion of the atherosclerotic plaque. In addition, oxidative stress-induced erythrocytes and endothelial cell arginase upregulation limit the pool for nitric oxide synthesis, leading to endothelial activation. Increased arginase activity may also lead to the formation of polyamines, which limit the deformability of red blood cells, hence facilitating erythrophagocytosis. Erythrocytes can also participate in the activation of platelets through the release of ADP and ATP and the activation of death receptors and pro-thrombin. Damaged erythrocytes can also associate with neutrophil extracellular traps and subsequently activate T lymphocytes. In addition, reduced levels of CD47 protein in the surface of red blood cells can also lead to erythrophagocytosis and a reduced association with fibrinogen. In the ischemic tissue, impaired erythrocyte 2,3 biphosphoglycerate, because of obesity or aging, can also favor hypoxic brain inflammation, while the release of damage molecules can lead to further erythrocyte dysfunction and death.

Investigating the Predictive Value of Thyroid Hormone Levels for Stroke Prognosis.

Given the expansion of life expectancy, the aging of the population, and the anticipated rise in the number of stroke survivors in Europe with severe neurological consequences in the coming decades, stroke is becoming the most prevalent cause of functional disability. Therefore, the prognosis for a stroke must be timely and precise. Two databases (MEDLINE and Scopus) were searched to identify all relevant studies published between 1 January 2005 and 31 December 2022 that investigated the relationship between thyroid hormone levels and acute stroke severity, mortality, and post-hospital prognosis. Only full-text English-language articles were included. This review includes Thirty articles that were traced and incorporated into the present review. Emerging data regarding the potential predictive value of thyroid hormone levels suggests there may be a correlation between low T3 syndrome, subclinical hypothyroidism, and poor stroke outcome, especially in certain age groups. These findings may prove useful for rehabilitation and therapy planning in clinical practice. Serum thyroid hormone concentration measurement is a non-invasive, relatively harmless, and secure screening test that may be useful for this purpose.

Targeting Neutrophil Extracellular Traps for Stroke Prognosis: A Promising Path.

Stroke has become the first cause of functional disability and one of the leading causes of mortality worldwide. Therefore, it is of crucial importance to develop accurate biomarkers to assess stroke risk and prognosis. Emerging evidence suggests that neutrophil extracellular trap (NET) levels may serve as a valuable biomarker to predict stroke occurrence and functional outcome. NETs are known to create a procoagulant state by serving as a scaffold for tissue factor (TF) and platelets inducing thrombosis by activating coagulation pathways and endothelium. A literature search was conducted in two databases (MEDLINE and Scopus) to trace all relevant studies published between 1 January 2016 and 31 December 2022, addressing the potential utility of NETs as a stroke biomarker. Only full-text articles in English were included. The current review includes thirty-three papers. Elevated NET levels in plasma and thrombi seem to be associated with increased mortality and worse functional outcomes in stroke, with all acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage included. Additionally, higher NET levels seem to correlate with worse outcomes after recanalization therapies and are more frequently found in strokes of cardioembolic or cryptogenic origin. Additionally, total neutrophil count in plasma seems also to correlate with stroke severity. Overall, NETs may be a promising predictive tool to assess stroke severity, functional outcome, and response to recanalization therapies.

Brain abscess in a rheumatoid arthritis patient treated with leflunomide - A case presentation and review.

BACKGROUND: Immunosuppression is a significant parameter in the pathogenesis of brain abscesses (BA) and it could be the result of severe infections such as acquired immunodeficiency syndrome or drug-induced, by several medications used for systemic autoimmune diseases. Leflunomide is a pyrimidine synthesis inhibitor that affects the proliferation of lymphocytes and is used as a disease-modifying antirheumatic drug. Mild infections, particularly those of the respiratory tract and herpes zoster, are one of its most common adverse effects. However, atypical and severe infections have also been reported under treatment with leflunomide. CASE DESCRIPTION: A 70-year old female was referred to our hospital with headache, aphasia, and right-sided hemiparesis and a lesion of the left parietal lobe initially interpreted as a malignancy. Her medical history revealed a 12-year old history of rheumatoid arthritis under current treatment with leflunomide. A cerebral magnetic resonance imaging (MRI) revealed typical findings for a BA. She subsequently underwent a left craniotomy, which confirmed the MRI-based diagnosis. The abscess was evacuated and cultures were obtained intraoperatively. In the postoperative examination, the patient showed no neurological deficit. CONCLUSION: The differential diagnostic considerations in immunocompromised patients with neurologic deficits should include focal central nervous system infections such as a BA, even in the absence of fever or immunosuppressant-induced leukopenia. It also demonstrates the importance of early neurosurgical intervention for the prevention of sequelae. To the best of our knowledge, this is the second-to-date reported case of a BA under immunomodulatory therapy with leflunomide.