Search Results

A significant proportion of individuals with human immunodeficiency virus (HIV) infection develop a neurological syndrome consisting of psychomotor retardation, dementia, and associated findings that was initially termed the acquired immunodeficiency syndrome (AIDS) dementia complex. This syndrome is now commonly known as HIV-associated dementia (HAD). This chapter discusses the clinical and pathological features, and pathophysiology in HIV-associated dementia, and the role of microglia in mediating neuronal injury in HIV infection.

This chapter begins by looking at the principal mechanisms of ischemic damage and identifies what is known about the specific contribution of glial cells. It then changes the perspective from affected tissue to single cells and reassesses the specific contribution of the glial cell types (astroglia, microglia, oligodendrocytes) in this process. Glial cells are major contributors to damage, as well as to endogenous protection and repair after stroke. The fact that the same cell types partake in damaging as well as protective signaling precludes simple therapeutic approaches aimed at blocking or inducing the activities of glial cells. Nevertheless, the recent appreciation of the high susceptibility of oligodendrocytes to AMPA-mediated cell death and the successful pilot trial on the use of EPO in stroke in humans are examples of the outstanding clinical relevance of glial mechanisms in stroke.

This chapter focuses on the contribution of activated microglia to the progression of Alzheimer's disease (AD) at various stages of the pathological cascade. Clusters of activated microglia occur only in complement-positive amyloidβ‎ (Aβ‎) plaques, and effector functions of complement include the modulation of microglial activity in vitro. It addresses the question of whether microglia are detrimental or beneficial in AD pathogenesis, especially in relation to the presence and modulating activities of activation products of the complement system.

This chapter shows the disease-specific, individual, and finely tuned reaction pattern of astrocytes and microglia during central nervous system (CNS) infections and their contribution to the intracerebral immune response. While both soluble mediators and the induction and/or upregulation of immunologically relevant cell surface molecules contribute to elimination of offending pathogens, microglia also serve an immunoregulatory function in order to minimize damage and destruction of vulnerable brain tissue. However, while these various components of the immune reaction serve a protective function, it is also evident that, depending on the underlying pathology, reactions of microglia and astrocytes may also be detrimental, as antibacterial effector molecules may also be neurotoxic and thereby contribute to neuronal damage, apoptosis, and, ultimately, long-term neurological sequelae.

This chapter focuses on microglial cells. Microglial cell numbers are thought to make up 5% to 20% of the entire central nervous system (CNS) glial cell population. As a conservative estimate, assuming that microglia represent 10% of the total glial cell pool and knowing that there are at least 10 times as many glial cells as there are neurons in the CNS, it is apparent that there are at least as many microglia as there are neurons. The origin and lineage of microglia, methods for staining microglia, microglia and related cell types, and microglia in the normal adult and aging brain are discussed.

Inflammation is a self-defensive reaction that may develop into a chronic state and become a causative factor in the pathogenesis of a broad range of disabling diseases. Similar to peripheral inflammation, brain inflammation is increasingly being viewed as a target for treating neurological diseases, not only infectious and immune-mediated disorders such as meningitis or multiple sclerosis but also stroke, trauma, and neurodegenerative diseases that were originally not considered to be inflammatory. Microglial cells, the resident macrophages of brain parenchyma, are generally viewed as major sources of pro-inflammatory and potentially neurotoxic molecules in the damaged brain, However, a direct link between activated microglia and tissue damage has not been univocally demonstrated in vivo, and recent studies have rather documented exacerbation of injury following selective microglial ablation or anti-inflammatory treatments. Recent studies have implicated inflammation in the regulation of adult neurogenesis, thus broadening the therapeutic potential of strategies aimed at controlling neuroinflammation. This chapter summarizes the main evidence supporting both detrimental and protective roles of inflammation in acute and chronic brain diseases.

Glia are recognized as active partners with neurons as participants in neurotransmission and they play essential roles in axonal conduction, synaptic plasticity, and information processing. In the adult human brain, glia outnumber neurons by one order of magnitude. There are two classes of glia: microglia (which mediate inflammatory responses in the central nervous system) and macroglia. Macroglia are oligodendrocytes and astrocytes. This chapter focuses on astrocytes, which are the most paradigmatic glia.

This chapter evaluates the different techniques for imaging of brain inflammation. The findings suggest that the spatial resolution of magnetic resonance spectroscopy (MRS) is relatively poor and remains to be improved, while brain imaging approaches using specific radioisotopes and positron emission tomography (PET) also have significant limitations. The results also indicate that in vivo imaging of activated microglia may be a potentially useful measure of the scope of possible functional rehabilitation and therapeutic efficacy in patients with brain injury.

This chapter examines the immune reactions of the central nervous system in Alzheimer's disease (AD), analysing the role of microglia in the mechanisms of inflammation in the AD brain and their relevance to new therapeutic strategies. It explains that the AD brain features a loss of neurones and neurites and that it also shows chronic accumulation of aggregated, highly insoluble amyloid beta deposits, and paired helical filaments.

In the avian brain, aromatase is constitutive and inducible in neurons and glia respectively. Glial aromatase is rapidly and dramatically upregulated in astroglia (astrocytes and radial glia) independent of brain region, in response to perturbation of the neuropil. Estrogens, synthesized by induced aromatization in glial cells, are potent mitigators of apoptotic degeneration and may accelerate neuronal replacement following brain damage. Specifically, aromatase inhibition increases, and estradiol replacement decreases secondary degeneration at the site of primary damage in the passerine brain. Indeed, the characteristic wave of secondary degeneration observed in mammals following compromise of the brain, is severely dampened in the passerine brain and is only revealed following inhibition of inducible glial aromatization. Further, the rate of injury-induced neurogenesis is increased in birds receiving estradiol replacement relative to those treated with an aromatase inhibitor alone. This chapter reviews data on the structural and functional consequences of glial aromatization. It highlights emerging data on the signals that invariably accompany brain damage and their potential role as inductive signals for the transcription and translation of the aromatase gene specifically in glial cells. The robust and cell-specific expression of aromatase in the passerine brain continues to provide an excellent model for the study of the provision of estrogens to neural targets with temporal and spatial specificity. In addition to basic scientific questions, passerine songbirds may serve as superb animal models toward understanding clinical syndromes involving brain damage, ischemia/anoxia, and neurodegeneration.

This chapter deals with the effect of systemic inflammation on neurodegenerative disease. It demonstrates that inflammation may contribute to Alzheimer’s disease (AD) progression. This chapter shows that the interactions between systemic inflammation and the microglia might have a profound influence on the acute and chronic phases of a neurodegenerative disease. It supports the hypothesis that systemic inflammation may accelerate the rate of decline in cognition in patients with AD. It shows that environmental enrichment can have a profound effect on the developing and diseased brain.

This chapter on estrogenic regulation of glia and neuroinflammation reviews the role of glial cells in the modulation of synaptic function under physiological conditions and in the regulation of the neuroinflammatory response under pathological conditions. The anti-inflammatory actions of estradiol on astrocytes, oligodendrocytes, and microglia and the implication of these actions for the neuroprotective and tissue repair effects of the hormone are also discussed. Finally, the therapeutic potential of synthetic and natural estrogenic compounds for the control of neuroinflammation is examined. Because reducing neuroinflammation prevents the progressive loss of neural structure and function that leads to functional and mental impairments, regulation of glial cell activation via estradiol is a promising therapeutic approach.

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.

I had the pleasure of meeting Channi Kumar as a junior psychiatry trainee at the Maudsley Hospital, when I elected to work in his clinical service as part of my rotation. It is therefore for me an honour to contribute to a book that celebrates his legacy. While working with him, I had the opportunity to seeing him in both the clinical and the academic settings. I came to know Channi as a gentle and charismatic clinician with patients, and an inspiring scientist. Channi was fascinated by the predictability of postpartum psychosis, which he used to discuss extensively with his patients, and he led seminal work on the biology of this disorder. I have been stimulated by this work and motivated to advance what remains a largely unexplored area of psychiatry. This chapter will discuss evidence on how biological factors relevant to the pathophysiology of psychoses and the perinatal period could interact in explaining the vulnerability and onset of postpartum psychosis. The role of genetic factors is extensively covered in Chapter 18, and will therefore not be discussed here. Psychiatric disorders contribute to 12% of all maternal deaths (UK Confidential Enquiry into Maternal Deaths; RCPG 2002), and puerperal (or postpartum) psychosis is the most severe psychiatric disorder associated with childbirth, with an estimated suicide rate of 2 per 1,000 sufferers (Oates 2003), and an incidence of 1–2/1,000 deliveries (Munk-Olsen et al. 2006). Although the last few decades have seen a fall in mortality and morbidity from childbirth, this has not been paralleled by a fall in the incidence of postpartum psychosis, which has remained remarkably stable at 0.5–1.0 per 1,000 deliveries (Munk-Olsen et al. 2006). Postpartum psychosis can have dramatic clinical and social consequences: child separation from the mother; lack of emotional bonding between mother and child; impaired child cognitive, physical, and psychological development; and, in some cases, suicide, infanticide, or both. This devastating impact is remarkable, especially considering that postpartum psychosis is highly predictable: in fact, between 30 and 50% of women with a history of bipolar affective disorder, or of schizoaffective disorder, will suffer postpartum psychosis after giving birth (Jones and Cradock 2001); and up to 50–70% of women with a previous history of postpartum psychosis (Jones and Craddock 2001).