The Long and the Short of it: Gene and Environment Interactions During Early Cortical Development and Consequences for Long-Term Neurological Disease

Cortical development is a complex amalgamation of proliferation, migration, differentiation, and circuit formation. These processes follow defined timescales and are controlled by a combination of intrinsic and extrinsic factors. It is currently unclear how robust and flexible these processes are and whether the developing brain has the capacity to recover from disruptions. What is clear is that there are a number of cognitive disorders or conditions that are elicited as a result of disrupted cortical development, although it may take a long time for the full pathophysiology of the conditions to be realized clinically. The critical window for the manifestation of a neurodevelopmental disorder is prolonged, and there is the potential for a complex interplay between genes and environment. While there have been extended investigations into the genetic basis of a number of neurological and mental disorders, limited definitive associations have been discovered. Many environmental factors, including inflammation and stress, have been linked to neurodevelopmental disorders, and it may be that a better understanding of the interplay between genes and environment will speed progress in this field. In particular, the development of the brain needs to be considered in the context of the whole materno-fetal unit as the degree of the metabolic, endocrine, or inflammatory responses, for example, will greatly influence the environment in which the brain develops. This review will emphasize the importance of extending neurodevelopmental studies to the contribution of the placenta, vasculature, cerebrospinal fluid, and to maternal and fetal immune response. These combined investigations are more likely to reveal genetic and environmental factors that influence the different stages of neuronal development and potentially lead to the better understanding of the etiology of neurological and mental disorders such as autism, epilepsy, cerebral palsy, and schizophrenia

Artificial intelligence-based decision support software to improve the efficacy of acute stroke pathway in the NHS: an observational study

IntroductionIn a drip-and-ship model for endovascular thrombectomy (EVT), early identification of large vessel occlusion (LVO) and timely referral to a comprehensive center (CSC) are crucial when patients are admitted to an acute stroke center (ASC). Several artificial intelligence (AI) decision-aid tools are increasingly being used to facilitate the rapid identification of LVO. This retrospective cohort study aimed to evaluate the impact of deploying e-Stroke AI decision support software in the hyperacute stroke pathway on process metrics and patient outcomes at an ASC in the United Kingdom.MethodsExcept for the deployment of e-Stroke on 01 March 2020, there were no significant changes made to the stroke pathway at the ASC. The data were obtained from a prospective stroke registry between 01 January 2019 and 31 March 2021. The outcomes were compared between the 14 months before and 12 months after the deployment of AI (pre-e-Stroke cohort vs. post-e-Stroke cohort) on 01 March 2020. Time window analyses were performed using Welch’s t-test. Cochran–Mantel–Haenszel test was used to compare changes in disability at 3 months assessed by modified Rankin Score (mRS) ordinal shift analysis, and Fisher’s exact test was used for dichotomised mRS analysis.ResultsIn the pre-e-Stroke cohort, 19 of 22 patients referred received EVT. In the post-e-Stroke cohort, 21 of the 25 patients referred were treated. The mean door-in-door-out (DIDO) and door-to-referral times in pre-e-Stroke vs. post-e-Stroke cohorts were 141 vs. 79 min (difference 62 min, 95% CI 96.9–26.8 min, p < 0.001) and 71 vs. 44 min (difference 27 min, 95% CI 47.4–5.4 min, p = 0.01), respectively. The adjusted odds ratio (age and NIHSS) for mRS ordinal shift analysis at 3 months was 3.14 (95% CI 0.99–10.51, p = 0.06) and the dichotomized mRS 0–2 at 3 months was 16% vs. 48% (p = 0.04) in the pre- vs. post-e-Stroke cohorts, respectively.ConclusionIn this single-center study in the United Kingdom, the DIDO time significantly decreased since the introduction of e-Stroke decision support software into an ASC hyperacute stroke pathway. The reduction in door-in to referral time indicates faster image interpretation and referral for EVT. There was an indication of an increased proportion of patients regaining independent function after EVT. However, this should be interpreted with caution given the small sample size. Larger, prospective studies and further systematic real-world evaluation are needed to demonstrate the widespread generalisability of these findings

The effects of cerebral ischaemia on pericytes and neurovascular function

Acute ischaemic stroke is a major cause of morbidity and mortality in the developed world, yet the treatment options available are limited to therapies that restore vessel patency. Recanalisation of the occluded artery does not necessarily result in reperfusion of the downstream microvasculature, however, and the pathomechanisms involved in this are incompletely understood. One putative mediator of this is the capillary pericyte, a vascular mural cell type that may constrict under ischaemic conditions. The overarching aim of this thesis was to characterise vascular function following cerebral ischaemia, using in vivo, ex vivo and in vitro approaches. First, I demonstrated that ischaemia reduced both ipsilateral and contralateral cerebral blood flow responses to hypercapnia, and diminished reactivity of isolated pressurised arteries. I then developed a novel assay to characterise human pericyte contractility in vitro, and demonstrated that they are responsive to vasoactive substances even in the absence of αSMA expression. In this assay, chemical ischaemia caused pericyte contraction and subsequent death, consistent with in vivo reports describing their role in the no-reflow phenomenon. Finally, I explored whether the voltage-gated Ca2+ channel antagonist nimodipine could improve reperfusion in cerebral ischaemia, and found that rats treated with nimodipine exhibited improved post-ischaemic cerebral blood flow and ameliorated neurological impairment. However, I did not find a direct effect of nimodipine on pericyte contractility during chemical ischaemia in vitro, indicating that nimodipine may be targeting other cell types in the vasculature. Together, these data highlight the importance of vascular function following stroke and shed light on putative vasculoprotective approaches, which have translational potential to improve reperfusion in patients receiving recanalisation therapy.</p

The effects of cerebral ischaemia on pericytes and neurovascular function

Acute ischaemic stroke is a major cause of morbidity and mortality in the developed world, yet the treatment options available are limited to therapies that restore vessel patency. Recanalisation of the occluded artery does not necessarily result in reperfusion of the downstream microvasculature, however, and the pathomechanisms involved in this are incompletely understood. One putative mediator of this is the capillary pericyte, a vascular mural cell type that may constrict under ischaemic conditions. The overarching aim of this thesis was to characterise vascular function following cerebral ischaemia, using in vivo, ex vivo and in vitro approaches. First, I demonstrated that ischaemia reduced both ipsilateral and contralateral cerebral blood flow responses to hypercapnia, and diminished reactivity of isolated pressurised arteries. I then developed a novel assay to characterise human pericyte contractility in vitro, and demonstrated that they are responsive to vasoactive substances even in the absence of &alpha;SMA expression. In this assay, chemical ischaemia caused pericyte contraction and subsequent death, consistent with in vivo reports describing their role in the no-reflow phenomenon. Finally, I explored whether the voltage-gated Ca2+ channel antagonist nimodipine could improve reperfusion in cerebral ischaemia, and found that rats treated with nimodipine exhibited improved post-ischaemic cerebral blood flow and ameliorated neurological impairment. However, I did not find a direct effect of nimodipine on pericyte contractility during chemical ischaemia in vitro, indicating that nimodipine may be targeting other cell types in the vasculature. Together, these data highlight the importance of vascular function following stroke and shed light on putative vasculoprotective approaches, which have translational potential to improve reperfusion in patients receiving recanalisation therapy.</p

Data_Sheet_1_Automated quantification of atrophy and acute ischemic volume for outcome prediction in endovascular thrombectomy.docx

BackgroundShort- and long-term outcomes from endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Numerous relevant predictors have been identified, including severity of neurological deficits, age, and imaging features. The latter is typically defined as acute changes (most commonly Alberta Stroke Programme Early CT Score, ASPECTS, at presentation), but there is little information on the impact of imaging assessment of premorbid brain health as a determinant of outcome.AimsTo examine the impact of automated measures of stroke severity and underlying brain frailty on short- and long-term outcomes in acute stroke treated with EVT.MethodsIn 215 patients with anterior circulation stroke, who subsequently underwent EVT, automated analysis of presenting non-contrast CT scans was used to determine acute ischemic volume (AIV) and e-ASPECTS as markers of stroke severity, and cerebral atrophy as a marker of brain frailty. Univariate and multivariate logistic regression were used to identify significant predictors of NIHSS improvement, modified Rankin scale (mRS) at 90 and 30 days, mortality at 90 days and symptomatic intracranial hemorrhage (sICH) following successful EVT.ResultsFor long-term outcome, atrophy and presenting NIHSS were significant predictors of mRS 0–2 and death at 90 days, whereas age did not reach significance in multivariate analysis. Conversely, for short-term NIHSS improvement, AIV and age were significant predictors, unlike presenting NIHSS. The interaction between age and NIHSS was similar to the interaction of AIV and atrophy for mRS 0–2 at 90 days.ConclusionCombinations of automated software-based imaging analysis and clinical data can be useful for predicting short-term neurological outcome and may improve long-term prognostication in EVT. These results provide a basis for future development of predictive tools built into decision-aiding software in stroke.</p

A systematic review and meta-analysis of randomized controlled trials of endovascular thrombectomy compared with best medical treatment for acute ischemic stroke

Acute ischemic strokes involving occlusion of large vessels usually recanalize poorly following treatment with intravenous thrombolysis. Recent studies have shown higher recanalization and higher good outcome rates with endovascular therapy compared with best medical management alone. A systematic review and meta-analysis investigating the benefits of all randomized controlled trials of endovascular thrombectomy where at least 25% of patients were treated with a thrombectomy device for the treatment of acute ischemic stroke compared with best medical treatment have yet to be performed