Stroke is the leading cause of disability in the United States and affects 15 million people worldwide. Studies performed in various parts of the world have found differences between sexes in stroke incidence, prevalence, mortality, and outcomes. Although men are at higher risk of stroke for most age groups below age 85 years, after this age the incidence reverses dramatically, with women being much more at risk. Furthermore, recent studies suggest that women have worse recovery than men post-stroke. Many aspects of recovery may influence this outcome, including sex-specific comorbidities, aggressiveness of acute treat-ment, prevention therapies, and varying degrees of social support and rates of depression. It is important to further define and investigate sex differences in stroke incidence, care, treatment, and outcomes to improve functional recovery in women.

Aging is a non modifiable risk factor for stroke. Since not all strokes can be prevented, a major emerging area of research is the development of effective strategies to enhance functional recovery after stroke. However, in the vast majority of pre-clinical stroke studies, the behavioral tests used to assess functional recovery have only been validated for use in young animals, or are designed for rats. Mice are increasingly utilized in stroke models but well validated behavioral tests designed for rats are not necessarily reproducible in mice. We examined a battery of behavioral tests to evaluate functional recovery in an aging murine model of stroke. We found that the vertical pole, hanging wire and open field can accurately assess acute behavioral impairments after stroke in both young and aging male mice, but animals recover rapidly on these tasks. The corner test can accurately and repeatedly differentiate stroke from sham animals up to 30 days post stroke and can be performed reliably in aging mice. Aging male mice had significantly worse behavioral impairment compared to young male mice in the first two weeks after stroke but eventually recovered to the same degree as young mice. In contrast, chronic infarct size, as measured by ipsilateral cerebral atrophy, was significantly lower in aging male mice compared to young male mice. Reactive gliosis, formation of glial scar, and an enhanced innate immune response was seen in the aging brain and may contribute to the delayed behavioral recovery seen in aged animals.

Stroke is a leading cause of permanent disability and death. It is well accepted that the principal mammalian estrogen (E2), 17-b estradiol, provides robust neuroprotection in a variety of brain injury models in animals of both sexes. E2 enhances neurogenesis after stroke in the subventricular zone; however, it is unknown if these cells survive long-term or enhance functional recovery. In this study, we examined stroke-induced neurogenesis in male, gonadally intact female, and ovariectomized female mice 2 and 6 weeks after stroke. Treatment with 17-b estradiol increased 5-bromo-2 0 -deoxyuridine-labeled cells at both time points in both the dentate gyrus and subventricular zone; the majority were colabeled with doublecortin at 2 weeks and with NeuN at 6 weeks. Stroke-induced neurogenesis was reduced in estrogen receptor knockout mice, as well as in mice lacking the gene for aromatase, which converts testosterone into E2. Improved behavioral deficits were seen in E2-treated mice, suggesting that E2-induced increases in poststroke neurogenesis contribute to poststroke recovery.

Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved energy sensor sensitive to changes in cellular AMP/ ATP ratio which is activated by phosphorylation (pAMPK). pAMPK levels decrease in peripheral tissues with age, but whether this also occurs in the aged brain, and how this contributes to the ability of the aged brain to cope with ischemic stress is unknown. This study investigated the activation of AMPK and the response to AMPK inhibition after induced stroke in both young and aged male mice. Baseline levels of phosphorylated AMPK were higher in aged brains compared to young mice. Strokeinduced a robust activation of AMPK in young mice, yet this response was muted in the aged brain. Young mice had larger infarct volumes compared with aged animals; however, more severe behavioral deficits and higher mortality were seen in aged mice after stroke. Inhibition of AMPK with Compound C decreased infarct size in young animals, but had no effect in aged mice. Compound C administration led to a reduction in brain ATP levels and induced hypothermia, which led to enhanced neuroprotection in young but not aged mice. This work demonstrates that aging increases baseline brain pAMPK levels; aged mice have a muted stroke-induced pAMPK response; and that AMPK inhibition and hypothermia are less efficacious neuroprotective agents in the aged brain. This has important translational relevance for the development of neuroprotective agents in preclinical models and our understanding of the enhanced metabolic stress experienced by the aged brain.

Purpose-While gender-affirming hormones (GAH) may impact the fertility of transgender and gender diverse (TGGD) youth, few pursue fertility preservation (FP). The objective of this study is to understand youth and parent attitudes toward FP decision-making.Methods-This study is a cross-sectional survey of youth and parents in a pediatric, hospitalbased gender clinic from April to December 2017. Surveys were administered electronically, containing 34 items for youth and 31 items for parents regarding desire for biological children, willingness to delay GAH for FP, and factors influencing FP decisions.Results-The mean age of youth (n = 64) was 16.8 years, and 64% assigned female at birth; 46 parents participated. Few youth (20%) and parents (13%) found it important to have biological children or grandchildren, and 3% of youth and 33% of parents would be willing to delay GAH for FP. The most common factor influencing youth FP decision-making was discomfort with a body part they do not identify with (69%), and for the parents, whether it was important to their child (61%). In paired analyses, youth and their parents answered similarly regarding youth desire for biological children and willingness to delay GAH for FP.Conclusions-The majority of TGGD youth and parents did not find having biological offspring important and were not willing to delay GAH for FP. Discomfort with reproductive anatomy was a major influencing factor for youth FP decision-making and their child's wishes was a major factor for parents. Future qualitative research is needed to understand TGGD youth and parent attitudes toward FP and to develop shared decision-making tools.