Sindi, Shireen

Abstract Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia‐related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex‐specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non‐disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex‐specific AD susceptibility and potential footholds for sex‐based interventions targeting these systems. We conclude by outlining immediate and long‐term actions to address the intersection of NSSs, sex, and AD.

Background The greatest potential to reduce the burden of stroke is by primary prevention of first-ever stroke, which constitutes three quarters of all stroke. In addition to population-wide prevention strategies (the ‘mass’ approach), the ‘high risk’ approach aims to identify individuals at risk of stroke and to modify their risk factors, and risk, accordingly. Current methods of assessing and modifying stroke risk are difficult to access and implement by the general population, amongst whom most future strokes will arise. To help reduce the burden of stroke on individuals and the population a new app, the Stroke Riskometer™, has been developed. We aim to explore the validity of the app for predicting the risk of stroke compared with current best methods. Methods 752 stroke outcomes from a sample of 9501 individuals across three countries (New Zealand, Russia and the Netherlands) were utilized to investigate the performance of a novel stroke risk prediction tool algorithm (Stroke Riskometer™) compared with two established stroke risk score prediction algorithms (Framingham Stroke Risk Score [FSRS] and QStroke). We calculated the receiver operating characteristics (ROC) curves and area under the ROC curve (AUROC) with 95% confidence intervals, Harrels C-statistic and D-statistics for measure of discrimination, R2 statistics to indicate level of variability accounted for by each prediction algorithm, the Hosmer-Lemeshow statistic for calibration, and the sensitivity and specificity of each algorithm. Results The Stroke Riskometer™ performed well against the FSRS five-year AUROC for both males (FSRS = 75·0% (95% CI 72·3%–77·6%), Stroke Riskometer™ = 74·0(95% CI 71·3%–76·7%) and females [FSRS = 70·3% (95% CI 67·9%–72·8%, Stroke Riskometer™ = 71·5% (95% CI 69·0%–73·9%)], and better than QStroke [males–59·7% (95% CI 57·3%–62·0%) and comparable to females = 71·1% (95% CI 69·0%–73·1%)]. Discriminative ability of all algorithms was low (C-statistic ranging from 0·51–0·56, D-statistic ranging from 0·01–0·12). Hosmer-Lemeshow illustrated that all of the predicted risk scores were not well calibrated with the observed event data ( P < 0·006). Conclusions The Stroke Riskometer™ is comparable in performance for stroke prediction with FSRS and QStroke. All three algorithms performed equally poorly in predicting stroke events. The Stroke Riskometer™ will be continually developed and validated to address the need to improve the current stroke risk scoring systems to more accurately predict stroke, particularly by identifying robust ethnic/race ethnicity group and country specific risk factors.