cerebrovascular dysfunction
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Mechanisms and consequences of cerebrovascular dysfunction in preeclampsia
PROJECT SUMMARY/ABSTRACT Preeclampsia (PE) is a common hypertensive disorder of pregnancy that causes significant maternal and fetal morbidity and mortality worldwide. PE women are at a high risk of stroke, including intracerebral hemorrhage, during the peripartum period, suggesting the sequelae of PE adversely impacts the cerebral circulation to promote hemorrhage. In addition, women with severe early-onset PE are at an 85-fold increased risk of death from intracerebral hemorrhage, importantly suggesting severity of disease promotes greater vulnerability of the cerebral circulation to degradation and rupture. However, the consequences of PE extend far beyond pregnancy and are associated with excessive cardiovascular and cerebrovascular disease risk later in life. Women with previous pregnancy complicated by PE can develop cognitive impairment as early as in their 30’s and 40’s, suggesting PE predisposes the brain to early-onset cognitive impairment. Studies have shown that formerly PE women have changes in gray matter volume and increased white matter lesion burden that occurs as a function of time from pregnancy, suggesting that PE continues to progressively damage the brain long after the affected pregnancy. Thus, our overall goal is to elucidate mechanisms by which women with PE are at risk of intracerebral hemorrhage in pregnancy and cognitive decline later in life. Our preliminary studies found greater vascular degradation, hematoma and cerebral edema in a model of severe PE that was associated with vascular inflammation and microglia activation (neuroinflammation). In addition, we found endothelial dysfunction and diminished neurovascular coupling in PE rats that persisted 5 months postpartum. Impaired neurovascular coupling is well-recognized as an underlying contributor to cognitive decline. These effects in postpartum animals with previous exposure to PE were associated with memory impairment that was not present in the pregnant state, suggesting neurovascular dysfunction precedes cognitive decline. Our central hypothesis is that the sequela of PE accelerates hypertension-induced cerebrovascular dysfunction that predisposes to intracerebral hemorrhage during pregnancy and its persistence postpartum results in early-onset cognitive decline. We will therefore elucidate mechanisms by which PE accelerates vascular degradation and worsens outcome from hemorrhagic stroke, probing pathways involved in oxidative degradative processes using multi-omics and multivariate analysis (Aim 1). We will also determine underlying molecular mechanisms that cause persistent cerebral microvascular dysfunction and cognitive decline postpartum, including oxidative stress-induced BBB leakage and persistent neuroinflammation that drives potassium channel dysfunction, reduced neurovascular coupling and neurovascular uncoupling (Aim 2). We will also use machine learning approaches together with multi-omics and outcome measures to identify factors and cellular pathways that are most impactful for prediction of intracerebral hemorrhage and cognitive impairment. The ability to predict and prevent devasting neurovascular disorders associated with PE has the potential to have long-lasting impacts on the lives of women with PE.
Obesity and Brain – Bidirectional Influences
The regulation of body weight relies on homeostatic mechanisms that use a combination of internal signals and external cues to initiate and terminate food intake. Homeostasis depends on intricate communication between the body and the hypothalamus involving numerous neural and hormonal signals. However, there is growing evidence that higher-level cognitive function may also influence energy balance. For instance, research has shown that BMI is consistently linked to various brain, cognitive, and personality measures, implicating executive, reward, and attentional systems. Moreover, the rise in obesity rates over the past half-century is attributed to the affordability and widespread availability of highly processed foods, a phenomenon that contradicts the idea that food intake is solely regulated by homeostasis. I will suggest that prefrontal systems involved in value computation and motivation act to limit food overconsumption when food is scarce or expensive, but promote over-eating when food is abundant, an optimum strategy from an economic standpoint. I will review the genetic and neuroscience literature on the CNS control of body weight. I will present recent studies supporting a role of prefrontal systems in weight control. I will also present contradictory evidence showing that frontal executive and cognitive findings in obesity may be a consequence not a cause of increased hunger. Finally I will review the effects of obesity on brain anatomy and function. Chronic adiposity leads to cerebrovascular dysfunction, cortical thinning, and cognitive impairment. As the most common preventable risk factor for dementia, obesity poses a significant threat to brain health. I will conclude by reviewing evidence for treatment of obesity in adults to prevent brain disease.
Adiponectin deficiency exacerbates cerebrovascular dysfunction in 5xFAD mouse model of Alzheimer’s disease
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