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This chapter examines the relation between the blood–brain barrier (BBB) and perivascular cells. It explains that the BBB is a dynamic interface between blood and brain which restricts the entry of plasma constituents that could interfere negatively with brain function while allowing substances which are essential for brain metabolism and function to enter the brain. The chapter discusses the structural basis for the BBB, the polarity of brain endothelial cells, and carrier-mediated transport of nutrients.

This chapter traces the development of the field of enzyme replacement. It explores the major remaining problem — i.e., treatment of lysosomal storage diseases with a major neurologic component, because of insulation of the brain from the therapeutic enzyme by the blood-brain barrier.

Cephalopod molluscs such as octopus, squid, and cuttlefish are among the most advanced invertebrates known, with large brains and highly developed sensory and motor capabilities. This chapter reviews recent high-resolution electron microscopic studies of the blood–brain interface in Sepia which demonstrate that the blood–brain barrier is formed by a novel restricting junction, between vascular pericytes in arterial vessels, and between perivascular glial cells in capillaries and venous vessels. The filtering properties of the junction appear to be determined by the extracellular matrix within the intercellular cleft, and a model is proposed by which adsorbed plasma proteins cross-link the matrix and reduce its effective mesh size. Electron microscopic examination of electron-dense tracer distribution in octopus and squid brains confirms that a blood–brain barrier to protein is also present in these groups. There is considerable variability in the structure and permeability of junctional zones in different tissues and species. This may reflect the combinations possible by subtle alterations in the two major components: the membranous elements of the junction and the material packing the intercellular cleft.

This chapter focuses on the potential roles of the sensory circumventricular organs in central autonomic control. These specialized structures are not only able to collect and integrate information but are also able to transmit output signals to autonomic control centers in the hypothalamus and the medulla. The chapter describes the specialized anatomical and physiological features of the sensory circumventricular organs and reviews an expanding literature that suggests important roles for these structures in the regulation of diverse autonomic systems controlling body fluids, metabolism, reproduction and immune regulation.

Stroke is the fifth leading cause of mortality and the major cause of long-term disability in the United States. Epidemiological studies report sex differences in ischemic stroke occurrence, mortality and functional recovery. In younger demographics, the overall incidence of stroke is higher in men than younger women, but in the elderly population, stroke rates are higher in older women compared to age-matched men, indicating an interaction of age and sex as important modifiers of disease. The increased risk for stroke in older women is attributed to loss of ovarian hormones, principally estrogens. However, estrogen/estradiol therapy is not always neuroprotective for stroke, especially in aging populations. Age-related changes in central and peripheral immune cells and the blood–brain barrier may play a crucial role in modifying stroke outcomes and the effects of estrogens. This chapter discusses the role of estrogens as a stroke protectant in younger females in contrast to its anomalous effects in the aging brain. Furthermore, the chapter describes age-related changes in support cells in the brain and in the periphery and evaluates the evidence that age-associated inflammation underlies the switch in estrogens neuroprotective action in young females to its neurotoxic effects in older females.

This chapter deals with brain temperature as a physiological parameter, which is determined primarily by neural metabolism, regulated by cerebral blood flow, and affected by various environmental factors and drugs. First, normal fluctuations in brain temperature that are induced by salient environmental stimuli and occur during motivated behavior at stable normothermic conditions are examined. On the basis of thermorecording data obtained in animals, the range of physiological fluctuations in brain temperature, their underlying mechanisms, and relations to body temperatures are described. The temperature dependence of neural activity and the dual “functions” of temperature as a reflection of metabolic brain activity and as a factor that affects this activity are considered. Third, pharmacological brain hyperthermia is discussed, focusing on the effects of psychomotor stimulants, highly popular drugs of abuse that increase brain metabolism, diminish heat dissipation, and may induce pathological brain overheating. The role of brain hyperthermia in leakage of the blood-brain barrier, development of brain edema, acute abnormalities of neural cells, and neurotoxicity, is also examined.

This chapter discusses antigen processing, presentation, and T cell interaction. The central nervous system (CNS) is protected by a blood-brain barrier (BBB) designed to minimize the passage of immune cells and macromolecules into the brain parenchyma. In the normal CNS parenchyma antigen-presenting cells (APCs) are functionally inactivated and lack expression of major histocompatibility complex (MHC) molecules. Nevertheless, the CNS is routinely surveyed by activated T lymphocytes. Perivascular macrophages situated adjacent to the endothelium cells of the blood vessels take up and present antigens to T lymphocytes. Most cells of the brain parenchyma are immunologically quiescent in the healthy CNS, but can be stimulated to become facultative APCs that process and present antigens via their MHC molecules to T lymphocytes in neuroinflammatory diseases.

Although the CNS has conventionally been viewed as an immunologically privileged site, the importance of immunological responses in the pathogenesis of CNS disease has become increasingly apparent over the last few decades. Indeed, the concept of CNS isolation from the immune system is hard to reconcile with the favourable outcome of encephalitides commonly complicating some exanthemata, such as mumps, and with the brisk cerebrospinal fluid pleocytosis, which almost invariably accompanies brain infection; neither observation suggests that CNS invasion by infective agents proceeds unhindered by immune response. However, whilst absolute immune privilege can no longer be sustained, is has become clear that there are fundamental differences between the mechanisms of immunity in the CNS and those elsewhere in the body. In order to understand the part inflammation plays in both pathogenesis and repair, it is necessary to consider briefly both the principles of the systemic immune response and the blood–brain barrier, which protects nervous tissues from the systemic circulation.

Neurodegenerative diseases lead to significant morbidity and mortality. Although medical care for other disorders (e.g., cardiovascular disease and cancer) has improved, neurodegenerative diseases have become more prevalent as the population ages. Understanding of the scientific underpinnings of neurodegenerative diseases has advanced greatly over the last thirty years. However, with a few exceptions, very few effective treatments are available to delay the onset or affect the course of these diseases. This Forum convened leaders in the field of neurodegeneration from different disciplines and tasked them with defining areas in need of more attention. A time frame of 5–20 years was the goal within which to develop more effective diagnostics and treatments. This chapter identifies eight key areas to address. With significant progress in each area, substantial changes in the diagnosis and treatment of neurodegenerative diseases should be possible over the next twenty years. Given the current cost of these diseases to society and the increase in their prevalence with no additional progress, a major worldwide effort should be made to address these issues immediately.

In multicellular organisms, thin lipid membranes serve as semipermeable barriers between aqueous compartments. The plasma membrane of the cell separates the cytoplasm from the extracellular space; endothelial cell membranes separate the blood within the vascular space from the rest of the tissue. Properties of the lipid membrane are critically important in regulating the movement of molecules between these aqueous spaces. While certain barrier properties of membranes can be attributed to the lipid components, accessory molecules within the cell membrane—particularly transport proteins and ion channels—control the rate of permeation of many solutes. Transport proteins permit the cell to regulate the composition of its intracellular environment in response to extracellular conditions. The relationship between membrane structure, membrane function, and cell physiology is an area of active, ongoing study. Our interest here is practical: what are the basic mechanisms of drug movement through membranes and how can one best predict the rate of permeation of an agent through a membrane barrier? To answer that question, this section presents rates of permeation measured in some common experimental systems and models of membrane permeation that can be used for prediction. The external surface of the plasma membrane carries a carbohydrate-rich coat called the glycocalyx; charged groups in the glycocalyx, which are provided principally by carbohydrates containing sialic acid, cause the surface to be negatively charged. On average, the plasma membrane of human cells contains, by mass, 50% protein, 45% lipid, and 5% carbohydrate. Given the mass ratio of protein to lipid is ~ 1 : 1, and assuming reasonable values for the average molecular weight and cross-sectional area for each type of molecule (50 × Mw,lipid = Mw,protein; Alipid = 50 Å2 and Aprotein = 1,000 Å2), the area fraction of protein on a typical membrane is ~ 33%. The lipid composition varies in membranes from different cells depending on the type of cell and its function. In addition, the outermost monolayer of lipids, called the outer leaflet, has a different lipid composition from the inner leaflet.

This chapter examines the influence of development on the inflammatory response in the central nervous system (CNS). It analyses the influence of the blood–brain barrier on brain inflammation, the leucocytes in the CNS, and the refractory nature of the brain. The findings suggest that while leucocyte traffic into the normal brain takes place as part of normal physiology, it is clear that the brain has evolved mechanisms to restrict the acute inflammatory response.

From the previous chapters you will see that understanding the pharmacological aspects of the drugs you are administering is vital to keeping your patients safe. Nurses need to understand the pharmacodynamics of a medicine, or how it actually works within the body, since this will need to be explained to patients and carers. For example, how will you ensure that a patient understands the importance of taking their treatment for hypertension (especially if they are experiencing no symptoms) if you are unable to explain how the medicine will be working? Similarly, your understanding of the pharmacokinetics (the absorption, distribution, metabolism, and excretion) of individual medicines is vital to ensure compromised patients are not administered inappropriate medicines. For example, you would question the prescribing of a non-steroidal anti-inflammatory drug (NSAID) to a patient with significant renal impairment, because the kidney is essential to the elimination of NSAIDs so the drug could accumulate if the kidneys are not functioning properly. From the point of view of ensuring patient safety, you will need to understand the principles of drug interactions so that you can understand how two medicines (or food and medicine) could interact and be alert to signs that this may be happening. There are several good textbooks dealing with the uses and actions of individual medicines, including interactions. However, these will not be discussed here because at this stage of your career you are not expected to have a detailed knowledge of particular medicines, but rather an understanding of the key principles. As nurses, we are concerned with how the body handles medicines (pharmacokinetics) so that we can see how this may be affected by age, genetics, or illness, and how the actions of medicines may conflict with one another or produce toxicity because their effects are additive. Equally, we need to look at occasions in which two medicines produce the same response by two different routes; such interactions can be beneficial to the patient and avoid having to give large doses of a single medicine because the same result can be achieved with smaller doses of two medicines, thereby reducing the risk of adverse effects.

Pesticides are often designed to interfere with the functions of the nervous system in pests, such as insects. But the brain biochemistry is similar in humans, and pesticide exposure can therefore cause toxicity to children’s brain development. This risk is almost never examined, however. When pregnant women are exposed at work or at home, the pesticides are shared with the fetus. Studies in several counties now show that community use of pesticides may harm brain development and cause lasting damage. We also know that over 200 chemicals, including many pesticides, solvents, metals and many other industrial compounds, can cause brain toxicity in adults. We must therefore assume that they are able to cross the blood-brain barrier and cause toxicity to developing brains. But even for pesticides designed to be neurotoxic, there is no systematic testing.

In this chapter, the current understanding of the mechanisms of endocrine disruption on the brain and nervous system are presented. Because the overwhelming majority of mechanistic studies on EDCs have focused on the actions mediated by nuclear hormone receptors, this mechanisms is described in detail. The chapter also discusses the classic transcriptional mechanisms of steroid action and the impact of EDCs on rapid signaling (non-genomic) mechanisms. It presents an overview of the enzymes and pathways involved in the biosynthesis of steroid hormones, which are critical to proper functioning of the HPA and HPG axis, and the neuroactive steroids synthesized and active in the mammalian brain. The potential for EDCs to alter metabolic enzymes, with a focus on possible targets in the metabolic blood-brain barrier, is presented as a potential, though largely unexplored, mode of EDC action in the brain.

Currently, a diagnosis of Alzheimer’s disease (AD) depends on some combination of the expression of telltale symptoms, patterns of performance obtained from neuropsychological tests, and brain imaging. Recognition that AD-related pathology can be ongoing for as much as a decade prior to the appearance of symptoms is the impetus behind a tremendous research effort aimed at identifying and developing biomarkers for AD that are linked to pathology and can be used for early disease screening, early diagnosis, and disease monitoring. The long list of recent failures of AD clinical trials has increased the intensity of the search for biomarkers that would make possible early detection and earlier enrollment into clinical trials, hopefully increasing the chances of a successful outcome. This chapter reviews progress along these lines, with emphasis on highlighting the various biomarkers found in the blood and cerebrospinal fluid that are relevant to the early pathology of AD.

This book has a combined focus on two neurodegenerative conditions: dementia with Lewy bodies and Parkinson’s disease with dementia. While patients with either disorder experience quite variable problems, these two disorders have striking similarities when viewed in the aggregate. Thus, the symptoms of these two conditions are much the same, and so are the treatment strategies. Before addressing treatment, it is crucial to define the relevant terms, broaden our understanding, and discuss how these diagnoses are made. We will start with some basics. These disorders typically start in middle age and later, where selected brain circuits deteriorate for unknown reasons. Common neurodegenerative conditions include Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease). Such conditions involve limited regions of the brain or spinal cord, slowly progressing and leading to disability. Each is clinically identified by the specific neurologic deficits unique to that condition. Why each affects certain brain regions, sparing others, is a crucial but unanswered question. Although much has been learned about degenerative syndromes, we do not know the causes of any of them. Dementia implies a loss of intellectual abilities sufficient to compromise activities of daily living. Most often the term dementia is used in the context of neurodegenerative disorders. Mild thinking and memory problems that do not substantially interfere with daily routines fall into the category of mild cognitive impairment (MCI; see below). Doctors diagnosing dementia rely on the history from the patient and family, plus cognitive tests. Short tests assessing memory, attention, and calculation, among other things, can be done in the doctor’s office. Such tests include the so-called Mini-Mental State Examination and the Short Test of Mental Status. More refined and informative tests, termed psychometric testing, are done under the auspices of psychologists; these typically require 2 to 4 hours. Clinicians addressing dementia must also look for treatable causes before concluding that the problem is a neurodegenerative dementia. This assessment typically includes a brain scan, blood tests, and a review of the patient’s medical history and medication list, which may indicate the need for additional testing.