Revealing the Influences of Sex Hormones and Sex Differences in Atrial Fibrillation and Vascular Cognitive Impairment

The impacts of sex differences on the biology of various organ systems and the influences of sex hormones on modulating health and disease have become increasingly relevant in clinical and biomedical research. A growing body of evidence has recently suggested fundamental sex differences in cardiovascular and cognitive function, including anatomy, pathophysiology, incidence and age of disease onset, symptoms affecting disease diagnosis, disease severity, progression, and treatment responses and outcomes. Atrial fibrillation (AF) is currently recognized as the most prevalent sustained arrhythmia and might contribute to the pathogenesis and progression of vascular cognitive impairment (VCI), including a range of cognitive deficits, from mild cognitive impairment to dementia. In this review, we describe sex-based differences and sex hormone functions in the physiology of the brain and vasculature and the pathophysiology of disorders therein, with special emphasis on AF and VCI. Deciphering how sex hormones and their receptor signaling (estrogen and androgen receptors) potentially impact on sex differences could help to reveal disease links between AF and VCI and identify therapeutic targets that may lead to potentially novel therapeutic interventions early in the disease course of AF and VCI.

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Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process

Brain Sciences ◽

10.3390/brainsci8090163 ◽

2018 ◽

Vol 8 (9) ◽

pp. 163 ◽

Cited By ~ 17

Author(s):

Caroline Gurvich ◽

Kate Hoy ◽

Natalie Thomas ◽

Jayashri Kulkarni

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Differences ◽

Cognitive Functioning ◽

Sex Hormones ◽

Reproductive Function ◽

Health And Disease ◽

And Function ◽

The Brain

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer’s disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer’s disease is also provided.

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The role of inflammasomes in vascular cognitive impairment

Molecular Neurodegeneration ◽

10.1186/s13024-021-00506-8 ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

Luting Poh ◽

Wei Liang Sim ◽

Dong-Gyu Jo ◽

Quynh Nhu Dinh ◽

Grant R. Drummond ◽

...

Keyword(s):

Cognitive Impairment ◽

Critical Role ◽

Disease Onset ◽

The Elderly ◽

Vascular Cognitive Impairment ◽

Cerebral Hypoperfusion ◽

Early Event ◽

Cellular Mechanisms ◽

Structural Brain Damage

AbstractThere 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-1β (IL-1β) 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-1β 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.

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Sex Disparities in Cystic Fibrosis: Review on the Effect of Female Sex Hormones on Lung Pathophysiology and Outcomes

ERJ Open Research ◽

10.1183/23120541.00475-2020 ◽

2020 ◽

pp. 00475-2020

Author(s):

G.Y. Lam ◽

J. Goodwin ◽

P.G. Wilcox ◽

B.S. Quon

Keyword(s):

Cystic Fibrosis ◽

Sex Differences ◽

Sex Hormones ◽

Mucociliary Clearance ◽

Therapeutic Interventions ◽

Female Sex ◽

Female Sex Hormones ◽

Sex Disparities

Sex differences in morbidity and mortality have been reported in the cystic fibrosis (CF) population worldwide. However, it is unclear why CF women have worse clinical outcomes than men. In this review, we focus on the influence of female sex hormones on CF pulmonary outcomes and summarise data from in vitro and in vivo experiments on how estrogen and progesterone might modify mucociliary clearance, immunity and infection in the CF airways. The potential for novel sex hormone related therapeutic interventions is also discussed.

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Temporal relations between atrial fibrillation and ischaemic stroke and their prognostic impact on mortality

EP Europace ◽

10.1093/europace/euz312 ◽

2019 ◽

Vol 22 (4) ◽

pp. 522-529 ◽

Cited By ~ 3

Author(s):

Stephan Camen ◽

Francisco M Ojeda ◽

Teemu Niiranen ◽

Francesco Gianfagna ◽

Julie K Vishram-Nielsen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cardiovascular Risk ◽

Ischaemic Stroke ◽

Temporal Relationship ◽

Cox Regression ◽

Systemic Disease ◽

Disease Onset ◽

Disease Diagnosis ◽

Prognostic Impact ◽

Temporal Relations

Abstract Aims Limited evidence is available on the temporal relationship between atrial fibrillation (AF) and ischaemic stroke and their impact on mortality in the community. We sought to understand the temporal relationship of AF and ischaemic stroke and to determine the sequence of disease onset in relation to mortality. Methods and results Across five prospective community cohorts of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project we assessed baseline cardiovascular risk factors in 100 132 individuals, median age 46.1 (25th–75th percentile 35.8–57.5) years, 48.4% men. We followed them for incident ischaemic stroke and AF and determined the relation of subsequent disease diagnosis with overall mortality. Over a median follow-up of 16.1 years, N = 4555 individuals were diagnosed solely with AF, N = 2269 had an ischaemic stroke but no AF diagnosed, and N = 898 developed both, ischaemic stroke and AF. Temporal relationships showed a clustering of diagnosis of both diseases within the years around the diagnosis of the other disease. In multivariable-adjusted Cox regression analyses with time-dependent covariates subsequent diagnosis of AF after ischaemic stroke was associated with increased mortality [hazard ratio (HR) 4.05, 95% confidence interval (CI) 2.17–7.54; P < 0.001] which was also apparent when ischaemic stroke followed after the diagnosis of AF (HR 3.08, 95% CI 1.90–5.00; P < 0.001). Conclusion The temporal relations of ischaemic stroke and AF appear to be bidirectional. Ischaemic stroke may precede detection of AF by years. The subsequent diagnosis of both diseases significantly increases mortality risk. Future research needs to investigate the common underlying systemic disease processes.

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Cognitive trajectories in multiple sclerosis: a long-term follow-up study

Neurological Sciences ◽

10.1007/s10072-021-05356-2 ◽

2021 ◽

Author(s):

Antonio Carotenuto ◽

Teresa Costabile ◽

Giuseppe Pontillo ◽

Moccia Moccia ◽

Fabrizia Falco ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Cognitive Rehabilitation ◽

Trajectory Analysis ◽

Disease Onset ◽

Disease Diagnosis ◽

Cognitive Status ◽

Grey Matter Volume ◽

Disease Course

Abstract Background Cognitive impairment occurs in multiple sclerosis (MS) and undergoes a progressive worsening over disease course. However, clinicians still struggle to predict the course of cognitive function. To evaluate baseline clinical and imaging predictors of cognitive abilities worsening over time, we performed a latent trajectory analysis for cognitive performances in MS patients, up to 15 years from disease onset. Methods We collected age, sex, education, dominant and non-dominant 9-hole peg test (9HP) and timed 25-foot walk (T25-FW) as well as MRI measures (grey matter volume and lesion load) within 6 months from disease diagnosis for relapsing–remitting MS (RR-MS) patients. At diagnosis and over the follow-up, we also assessed cognitive status through the symbol digit modalities test (SDMT). Cognitive impairment was defined by applying age-, gender- and education-adjusted normative values. Group-based trajectory analysis was performed to determine trajectories, and the predictive value of clinical and imaging variables at baseline was assessed through multinomial logistic regression. Results We included 148 RR-MS (98 females and 50 males). Over 11 ± 4 year follow-up, 51.4% remained cognitively stable whereas 48.6% cognitively worsened. Cognitively worsening patients had a higher T25FW time (p = 0.004) and a reduced hippocampal volume at baseline (p = 0.04). Conclusion Physical disability as well as hippocampal atrophy might depict patients at risk of cognitive worsening over the disease course. Therefore, using such predictors, clinicians may select patients to carefully evaluate for cognitive impairment as to eventually introduce cognitive rehabilitation treatments.

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Sex differences in memory clinic patients with possible vascular cognitive impairment

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring ◽

10.1002/dad2.12090 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Lieza G. Exalto ◽

Jooske M. F. Boomsma ◽

Rosha Babapour Mofrad ◽

Frederik Barkhof ◽

Onno N. Groeneveld ◽

...

Keyword(s):

Sex Differences ◽

Cognitive Impairment ◽

Vascular Cognitive Impairment ◽

Memory Clinic

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Sex hormones underlying 17a-Estradiol effects on neuroinflammation

10.1101/2020.05.26.117689 ◽

2020 ◽

Author(s):

Lucas K. Debarba ◽

Hashan Jayarathne ◽

Richard A. Miller ◽

Michael Garratt ◽

Marianna Sadagurski

Keyword(s):

Sex Hormones ◽

Disease Onset ◽

Brain Regions ◽

Gonadal Hormone ◽

Sexually Dimorphic ◽

Hormone Production ◽

Specific Effects ◽

Hypothalamic Inflammation ◽

Health And Disease ◽

Male Specific

Abstract17-α-estradiol (17aE2) treatment extends lifespan in male mice and can reduce neuroinflammatory responses in the hypothalamus of 12-month-old males. Although 17aE2 improves longevity in males, female mice are unaffected, suggesting a sexually dimorphic pattern of lifespan regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are mediated by sex hormones and whether hypothalamic changes extend to other brain regions in old age. Manipulating sex hormone levels through gonadectomy, we show that sex-specific effects of 17aE2 on age-associated gliosis are brain region-specific and are partially dependent on gonadal hormone production. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration prior to 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis. By contrast, sex-specific changes in microgliosis with 17aE2 were not significantly affected by castration in males. While 17aE2 treatment had no effect of hypothalamic astrocytes or microglia in intact females, ovariectomy significantly increased the occurrence of hypothalamic gliosis evaluated in 25-month-old females, which was partially reduced by 17aE2. In the hippocampus, both male and female gonadally-derived hormones influenced the severity of gliosis and the responsiveness to 17aE2 in a regiondependent manner. The male-specific effects of 17aE2 correlate with changes in hypothalamic ERα expression, highlighting a receptor through which 17aE2 could act. The results of this study demonstrate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Interactions between sex-steroids and neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in aging.

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