Hypertension & dementia: Pathophysiology & potential utility of antihypertensives in reducing disease burden.

Dementia is a common cause of disability and dependency among the elderly due to its progressive neurodegenerative nature. As there is currently no curative therapy, it is of major importance to identify new ways to reduce its prevalence. Hypertension is recognised as a modifiable risk factor for dementia, particularly for the two most common subtypes; vascular dementia (VaD) and Alzheimer's disease (AD). From the current literature, identified through a comprehensive literature search of PubMed and Cochrane Library, this review aims to establish the stage in adulthood when hypertension becomes a risk for cognitive decline and dementia, and whether antihypertensive treatment is effective as a preventative therapy. Observational studies generally found hypertension in mid-life (age 45-64) to be correlated with an increased risk of cognitive decline and dementia incidence, including both VaD and AD. Hypertension manifesting in late life (age ≥ 65) was demonstrated to be less of a risk, to the extent that incidences of high blood pressure (BP) in the very elderly (age ≥ 75) may even be related to reduced incidence of dementias. Despite the evidence linking hypertension to dementia, there were conflicting findings as to whether the use of antihypertensives was beneficial for its prevention and this conflicting evidence and inconsistent results could be due to the methodological differences between the reviewed observational and randomised controlled trials. Furthermore, dihydropyridine calcium channel blockers and potassium-sparing diuretics were proposed to have neuroprotective properties in addition to BP lowering. Overall, if antihypertensives are confirmed to be beneficial by larger-scale homogenous trials with longer follow-up durations, treatment of hypertension, particularly in mid-life, could be an effective strategy to considerably lower the prevalence of dementia. Furthermore, greater clarification of the neuroprotective properties that some antihypertensives possess will allow for better clinical practice guidance on the choice of antihypertensive class for both BP lowering and dementia prevention.

Polypathologies and Animal Models of Traumatic Brain Injury.

Traumatic brain injury (TBI) is an important health issue for the worldwide population, as it causes long-term pathological consequences for a diverse group of individuals. We are yet to fully elucidate the significance of TBI polypathologies, such as neuroinflammation and tau hyperphosphorylation, and their contribution to the development of chronic traumatic encephalopathy (CTE) and other neurological conditions. To advance our understanding of TBI, it is necessary to replicate TBI in preclinical models. Commonly used animal models include the weight drop model; these methods model human TBI in various ways and in different animal species. However, animal models have not demonstrated their clinical utility for identifying therapeutic interventions. Many interventions that were successful in improving outcomes for animal models did not translate into clinical benefit for patients. It is important to review current animal models and discuss their strengths and limitations within a TBI context. Modelling human TBI in animals encounters numerous challenges, yet despite these barriers, the TBI research community is working to overcome these difficulties. Developments include advances in biomarkers, standardising, and refining existing models. This progress will improve our ability to model TBI in animals and, therefore, enhance our understanding of TBI and, potentially, how to treat it.

Extracellular vesicles and their microRNA cargo in ischaemic stroke.

Acute ischaemic stroke (AIS) is a leading cause of death and disability. MicroRNAs (miRNAs) are short non-coding RNAs which hold the potential to act as a novel biomarker in AIS. The majority of circulating miRNAs are actively encapsulated by extracellular vesicles (EVs) produced by many cells and organs endogenously. EVs released by mesenchymal stem cells (MSCs) have been extensively studied for their therapeutic potential. In health and disease, EVs are vital for intercellular communication, as the cargo within EVs can be exchanged between neighbouring cells or transported to distant sites. It is clear here from both current preclinical and clinical studies that AIS is associated with specific EV-derived miRNAs, including those transported via MSC-derived EVs. In addition, current studies provide evidence to show that modulating levels of specific EV-derived miRNAs in AIS provides a novel therapeutic potential of miRNAs in the treatment of stroke. Commonalities exist in altered miRNAs across preclinical and clinical studies. Of those EV-packaged miRNAs, miRNA-124 was described both as an EV-packaged biomarker and as a potential EV-loaded therapeutic in experimental models. Alterations of miRNA-17 family and miRNA-17-92 cluster were identified in preclinical, clinical and MSC-EV-mediated neuroprotection in experimental stroke. Finally, miRNA-30d and -30a were found to mediate therapeutic effect when overexpressed from MSC and implicated as a biomarker clinically. Combined, EV-derived miRNAs will further our understanding of the neuropathological processes triggered by AIS. In addition, this work will help determine the true clinical value of circulating EV-packaged miRNAs as biomarkers of AIS or as novel therapeutics in this setting.

Systematic review: Association between circulating microRNA expression & stroke.

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.