Hope for vascular cognitive impairment: Ac-YVAD-cmk as a novel treatment against white matter rarefaction.

Vascular cognitive impairment (VCI) is the second leading cause of dementia with limited treatment options, characterised by cerebral hypoperfusion-induced white matter rarefaction (WMR). Subcortical VCI is the most common form of VCI, but the underlying reasons for region susceptibility remain elusive. Recent studies employing the bilateral cortical artery stenosis (BCAS) method demonstrate that various inflammasomes regulate white matter injury and blood-brain barrier dysfunction but whether caspase-1 inhibition will be beneficial remains unclear. To address this, we performed BCAS on C57/BL6 mice to study the effects of Ac-YVAD-cmk, a caspase-1 inhibitor, on the subcortical and cortical regions. Cerebral blood flow (CBF), WMR, neuroinflammation and the expression of tight junction-related proteins associated with blood-brain barrier integrity were assessed 15 days post BCAS. We observed that Ac-YVAD-cmk restored CBF, attenuated BCAS-induced WMR and restored subcortical myelin expression. Within the subcortical region, BCAS activated the NLRP3/caspase-1/interleukin-1beta axis only within the subcortical region, which was attenuated by Ac-YVAD-cmk. Although we observed that BCAS induced significant increases in VCAM-1 expression in both brain regions that were attenuated with Ac-YVAD-cmk, only ZO-1 and occludin were observed to be significantly altered in the subcortical region. Here we show that caspase-1 may contribute to subcortical regional susceptibility in a mouse model of VCI. In addition, our results support further investigations into the potential of Ac-YVAD-cmk as a novel treatment strategy against subcortical VCI and other conditions exhibiting cerebral hypoperfusion-induced WMR.

The role of inflammasomes in vascular cognitive impairment.

There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1ß (IL-1ß) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1ß production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

MicroRNAs in chronic airway diseases: Clinical correlation and translational applications.

MicroRNAs (miRNAs) are short single-stranded RNAs that have pivotal roles in disease pathophysiology through transcriptional and translational modulation of important genes. It has been implicated in the development of many diseases, such as stroke, cardiovascular conditions, cancers and inflammatory airway diseases. There is recent evidence that miRNAs play important roles in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and could help to distinguish between T2-low (non-eosinophilic, steroid-insensitive) versus T2-high (eosinophilic, steroid-sensitive) disease endotypes. As these are the two most prevalent chronic respiratory diseases globally, with rising disease burden, miRNA research might lead to the development of new diagnostic and therapeutic targets. Research involving miRNAs in airway disease is challenging because: (i) asthma and COPD are heterogeneous inflammatory airway diseases; there are overlapping but distinct inter- and intra-disease differences in the immunological pathophysiology, (ii) there exists more than 2000 known miRNAs and a single miRNA can regulate multiple targets, (iii) differential effects of miRNAs could be present in different cellular subtypes and tissues, and (iv) dysregulated miRNA expression might be a direct consequence of an indirect effect of airway disease onset or progression. As miRNAs are actively secreted in fluids and remain relatively stable, they have the potential for biomarker development and therapeutic targets. In this review, we summarize the preclinical data on potential miRNA biomarkers that mediate different pathophysiological mechanisms in airway disease. We discuss the framework for biomarker development using miRNA and highlight the need for careful patient characterization and endotyping in the screening and validation cohorts, profiling both airway and blood samples to determine the biological fluids of choice in different disease states or severity, and adopting an untargeted approach. Collaboration between the various stakeholders - pharmaceutical companies, laboratory professionals and clinician-scientists is crucial to reduce the difficulties and cost required to bring miRNA research into the translational stage for airway diseases.

Clinical characteristics and outcomes of octogenarians presenting with ST elevation myocardial infarction in the Australian population.

AIM: To investigate the characteristics and outcomes of octogenarians who presented with ST-elevation myocardial infarction (STEMI) compared to non-octogenarians and to investigate the outcomes of octogenarians that received primary percutaneous coronary intervention (PCI) compared to those managed conservatively. METHODS: We performed a single center retrospective case controlled study. All octogenarians who presented with STEMI to a tertiary referring hospital between 2007 and 2012 were included. The subsequent non-octogenarian patient who presented with a STEMI following the octogenarian patient was assigned to the control group in a 1:1 manner. The outcomes measured were peri-procedural cardiac arrest, death on table, cerebrovascular accidents (CVA), in-hospital and 30-d mortality. RESULTS: A total of 146 patients were analyzed. The octogenarian group had a higher percentage of females, higher overall comorbidities, higher Charlson Comorbidity Index score, worse renal function and were more likely to require residential care and home help. The octogenarian group were also less likely to have PCI attempted and had a longer symptom onset to PCI time. Mortality rate was high amongst octogenarians who presented with STEMI. However, those managed conservatively had a higher in-hospital and 30-d mortality rate. CONCLUSION: Octogenarians who presented with STEMI that were managed conservatively had a higher mortality rate compared to those who had primary PCI. Therefore, we propose that revascularization may be beneficial to patients in this age group.