Exploring sex differences in the association between cerebral small vessel disease, hypertension and cognitive decline

It is established now that hypertension, cerebral small vessel disease (cSVD) and cognitive decline are highly associated. Hypertension is indisputably one of the most important vascular risk factors for cognitive decline 1, whilst also being a significant risk factor for cSVD. cSVD, referring to dysfunction of microvessels within the brain, also strongly correlates with cognitive decline 2. In the current edition of the Journal of Hypertension, Kaur et al.3 discuss the significant overlap between factors, specifically investigating the potential effects of sex on hypertension, cSVD and cognitive decline, aiming to uncover sex-specific therapeutic avenues. The authors included over 60 articles discovered through an in-depth literature search on major databases. Key identifiers included: sex differences, hypertension, cerebral small vessel disease and cognitive decline, and publications were limited to those post-1990. To ensure specificity of the included publications, papers referring to Parkinson's disease, Alzheimer's, dementia or diagnostic techniques were excluded from the study. Discussing literature and revealing associations between hypertension and cognitive decline, the review highlights the strong negative correlation observed between hypertension and cognitive performance, an association which is strengthened with increased age 4. Numerous studies all support this correlation. These studies, however, fail to encapsulate the potential effects of sex differences on risk of cognitive decline. Previous research has revealed significant differences in blood pressure between males and females, at a range of ages, finding that during puberty, male blood pressure was significantly higher, compared to females 5. However, over the age of 60, there is a significantly greater prevalence of hypertension in the female population, likely due to the steeper age-related rate of hypertension diagnosis that is observed in females. These differences are highlighted by the authors, stressing the importance of potential sex-specific mechanisms. The authors investigated the effects of hormones, pregnancy and menopause on hypertension and cognitive decline as an explanation for sex-differences in blood pressure. Due to the strong association between hypertension and cSVD, the authors also examined potential variation of cSVD between sexes. Differences between the sexes is seen in both the prevalence of cSVD and the nature of brain lesions, with the most notable difference being a larger volume of white matter hyperintensities in women 6, compared with a greater number of lacunar and cortical infarcts in males. Current literature points towards an increased risk of hypertension, cSVD and cognitive decline in women, but the causes of these differences in brain health between the sexes remains unclear. This review is timely, therefore, highlighting the necessity for further research to understand the cause of these differences. The compilation of evidence outlining significant differences in pathophysiology in women compared to men is an important addition to the literature reinforcing the importance of ongoing research tailored towards sex-specific research. It also promotes the possibility to uncover sex-specific approaches to reducing hypertension and the risk of cSVD, aiming to reduce cognitive decline in both sexes in the most efficient manner possible. Overall, the authors offer encouraging evidence that researching hypertension, cSVD and cognitive decline in a sex-specific manner could significantly further current understanding of disease pathophysiology and provide novel targets for therapeutic intervention. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.