Leukaemias These are the most common cause of malignant disease in children. However, leukaemia can develop at any age and, in most countries, the majority of people who get leukaemia are over the age of 55. The commonest childhood leukaemia is acute lymphocytic leukaemia whereas aging adults tend to get chronic granulocytic leukaemia. There are multiple factors that cause leukaemias, but there are some groups of people who are more likely to get them. These include people exposed to ionising radiations or to certain chemicals, or those born with particular congenital abnormalities. Characteristically, there is a problem in the production of new blood cells in the bone marrow of the body. The most primitive blood cells in the series develop faults, and they cannot be induced to change normally into mature forms which should circulate in the blood. These immature, malfunctioning cells accumulate in the bone marrow, and upset normal blood cell development. Thus the blood may contain fewer cells than normal of a particular type, and in addition a few leukaemic cells may escape into the blood. So an examination of the blood in patients reporting aching and tender bones, enlarged joints or severe anaemia is generally followed by an examination of the bone marrow to see if abnormal cells are present there. Often in acute leukaemia the lymph nodes and spleen swell. Treatment of leukaemias today is quite effective, but death may result from secondary problems such as infections, bleeding and failure of the kidneys and/or liver.

Future travels Visitors to a new environment are advised to protect themselves against unfamiliar pathogens. How wise is one to ignore such health recommendations? Why is it that the local inhabitants in these countries do not take the same precautions as visitors? Every individual, whilst growing up, is exposed to most of the pathogens of his/her local environment. We have already seen that mother's milk gives some protection to the newborn whilst the baby's immune system is developing. Then a baby born to a family that has stayed in one environment for several generations may inherit genes that have been selected for by their ability to give protection against locally occurring pathogens. In modern society though, there is so much more movement between countries than there was during the periods of human evolution, that genetic recombination is probably of less importance in practice than in theory. However, most children in western societies will be exposed to common colds and other common infections during childhood, and will adapt their immune system to cope with repeat challenges. Even more serious pathogens such as the tuberculosis bacillus are present in western society and many adults have been exposed to it, and gained some immunity. Thus the immune system is learning all the time which pathogens are around. Flying away for holidays or work to a completely new location means that suddenly the body is faced with new challenges it has not met before.

Acquired Immunodeficiency Syndrome (AIDS) AIDS patients are severely immunocompromised, since the human immunodeficiency virus (HIV) attacks many of the immune system cells and destroys them. As a result, the patient cannot fight off any pathogens that enter the body through the skin or other major ports of entry, such as the mouth, anus, eyes and sweat glands. Nor can the patient combat uncontrolled growth of cancerous cells within the body. In the initial stages of an HIV infection, before any serious problems are suspected, the skin may have a transient rash. As the disease progresses, patients may develop a number of skin conditions, such as dermatitis around the sebaceous glands of hairs, persistent genital ulcers, and eczema. Fungi such as Candida albicans, which can affect many healthy people without harming them, become a problem and cannot be controlled. Later on in the HIV infection, many patients have shingles, and the serious skin and connective tissue cancer, Kaposi's syndrome, takes hold. This is seen as pink/purple blotches on the skin which may ulcerate, and swellings caused by enlarged lymph nodes. As many as 40% of homosexual patients with AIDS develop Kaposi's syndrome, yet in healthy men that are not infected with HIV it is rare and only occurs in older men of certain Mediterranean origins. In Africa, both men and women may develop Kaposi's syndrome in AIDS.

Rejecting transplants The techniques involved with modern transplantation surgery are very good today, allowing a wide range of organs to be successfully replaced. However, the patient's own body has unique methods of recognising and acting against bacteria, viruses or many foreign invaders in order to overcome them. The same reactions take place against donor organs since they come from a different body, so powerful drugs are used to reduce these natural, usually beneficial, reactions that are potentially harmful in transplantation surgery. Of great importance is the genetic similarity or dissimilarity between donor and recipient. If a group of genes, known as the histocompatibility genes, are identical in both donor and recipient, then there would be no problems of transplant tissue being rejected. Since all individuals inherit some genes from each parent, the resultant genes in the child will not exactly match those of either parent or any brothers and sisters. So, no two individuals, except identical twins where the fertilised egg was split into two, will have the same set of genes (their genetic make-up). Surprisingly, the immune system's cells can recognise the differences and, as a result, the transplant can be destroyed. In order to ensure success after surgery, the body's own immune system must be dampened down to minimise the chances of any cells reacting to the graft and causing rejection. The patient is therefore very susceptible to infections and diseases during this period, and to cancers in the longer term.

Multiple sclerosis What causes multiple sclerosis is still a mystery, but the strange geographical distribution of its appearance in clusters in certain populations, similar major histocompatibility complex (MHC) genes in many of those affected, more IgG in blood during an attack, autoantibodies to the myelin of the fatty sheath around nerves, and evidence from animals studies of a closely related condition suggest an infectious basis. A common early symptom is inflammation of the nerve to one eye, more often in young women than in children. The disease characteristically flares up in episodes with remissions in between. However, with time, it tends to become relentlessly progressive. The nervous tissue of the brain and spinal column develops hardened regions termed plaques. Here the nerves have lost their fatty protective covering, or sheath, of myelin and there is a strong infiltration of leukocytes into the brain, particularly in the newly formed plaques. This is unusual as brain cells normally restrict the entry of leukocytes by a blood-brain barrier formed from cells within the brain. When this barrier is penetrated, then large numbers of immune cells can enter. Whether these infiltrating cells are making the disease worse or controlling it is unclear. The loss of the myelin sheath results in poor nerve impulse transmission, so that the most devastating practical result of this disease is difficulty in walking.

Malaria Most people will have heard of malaria. It was called Jungle fever in World War II, and Marsh fever by ancient Britons. All travellers are warned to protect themselves if they are visiting a malaria area, such as Africa, Asia, Central America and South America. Other more temperate countries like the United Kingdom can also have malaria outbreaks but these are largely past history. The World Health Organisation has estimated that there are probably 300–500 million cases of malaria a year. This means that it is one of the most prevalent and severe diseases of the tropics. The malaria parasite shares its complex life style with Man and an insect vector, the Anopheles mosquito. Mosquitoes can move over large areas of land and take blood from other animals, as well as Man. There are many forms of malaria and several vectors, but all cause cycles of fever and attack red blood cells. Chronic malaria can result in profound anaemia, loss of weight, depression, enlargement of the spleen, muscular weakness and oedema or fluid retention in places such as the ankles. Cerebral malaria is often fatal. Prophylactic medicines protect travellers, but must be started before travelling and continued afterwards. There are no good vaccines at present, although several have been tested. Until these are available, protecting oneself from being bitten by mosquitoes in endemic areas is still the best way to avoid the disease.

Summary

Neurochemical pathology associated with alterations in consciousness in Lewy body dementia (LBD) is discussed in relation to cholinergic and monoaminergic systems projecting to the cortex. Extensive loss of cholinergic activity from neocortical areas in hallucinating <B>LBD cases is consistent with the ability of anticholinergic drugs (antimuscarinics such as scopolamine) to induce similar types of hallucinations in normal individuals. Evidence is reviewed which suggests the M4 muscarinic subtype, which is particularly high in primate visual cortex and is activated by the atypical neuroleptic clozapine, may be involved in atropine psychosis. The possible role of non-cortical areas such as the brainstem reticular activating system in abnormal conscious activity in LBD is also considered, as is the involvement of the cholinergic system in schizophrenic psychosis. Amongst a range of potential approaches to cholinergic therapy in LBD, it is argued that stimulation of the nicotinic cholinergic receptor may be particularly useful since this may benefit both cognitive and motor dysfunction and also provide some degree of neuroprotection.

Introduction

‘Consciousness: the having of perceptions, thoughts, and feelings awareness. The term is impossible to define except in terms that are unintelligible, without a grasp of what consciousness means. Consciousness is a fascinating but elusive phenomenon: it is impossible to specify what it is, what it does or why it evolved. Nothing worth reading has been written about it’ (Sutherland, 1989).

The bridge between mind and brain in dementing disorders such as Alzheimer's disease (AD), has generally been supported by objective measures of memory loss and related cognitive impairment, or psychotic features such as depression and aggression which also have overt behavioural counterparts.

Summary

Recent clinico-neuropathological studies have shown that approximately 25% of patients who manifest a syndrome similar to dementia of the Alzheimer type during life have diffuse Lewy body disease (DLBD), a condition characterized by neocortical and subcortical Lewy body pathology that occurs, in many cases, along with the typical cortical distribution of senile plaques and neurofibrillary tangles associated with Alzheimer's disease (AD). Studies of the neuropsychology of this disorder demonstrate that DLBD, without concomitant AD, can produce a global dementia characterized by particularly pronounced deficits in memory (i.e. retrieval), attention, visuospatial abilities and psychomotor speed. When both DLBD and AD pathology is present, patients exhibit severe deficits in memory, language, and executive functions, most likely due to the severe hippocampal and neocortical damage that occurs in AD, as well as particularly severe deficits in visuospatial abilities, attention, and psychomotor processes, which may reflect the additive effects of Lewy body pathology. This pattern of neuropsychological deficits has also been observed in recent prospective studies of patients with clinically diagnosed DLBD, and may prove to be an important addition to the diagnostic criteria for DLBD.

Introduction

Recent clinico-neuropathological studies have shown that approximately 25% of patients who manifest a syndrome similar to dementia of the Alzheimer type during life have Lewy bodies diffusely distributed throughout the neocortex (for review, see Hansen & Galasko, 1992). This cortical Lewy body pathology occurs along with the typical subcortical changes of Parkinson's disease (i.e. Lewy bodies and cell loss) in the substantia nigra and other pigmented brainstem nuclei, and in many cases with the typical cortical distribution of senile plaques and neurofibrillary tangles associated with Alzheimer's disease (AD) (Hansen et al., 1990).

Summary

Altered processing of tau protein is a characteristic feature of Alzheimer's disease (AD) that, unlike the accumulation of amyloid β-protein, is strongly correlated with clinical dementia. In AD, tau is substantially redistributed from its soluble, predominantly axonal form into insoluble PHF-tau that accumulates in the somatodendritic compartment. Although hyperphosphorylated tau also accumulates, this accounts for no more than 5% of the total PHF-tau during any stage of the development of AD. In contrast, cortical Lewy body dementia in the elderly is not associated with these changes in tau processing and such patients have less than one-tenth of the levels of both PHF-tau and neurofibrillary pathology as those found in AD. These findings support the notion that the pathobiology of these two disorders is distinct and provide the opportunity to compare non-PHF- with PHF-type dementias. Both these late-onset dementias are associated with comparable increases in the frequency of the apolipoprotein E (APO E) type ∈4 allele (in excess of 30%, as compared with 14% in controls and 10% in Parkinson's disease). The extent of abnormal PHF-tau levels in AD is unaffected by the presence of an e4 allele, suggesting that APO E polymorphisms do not directly influence the pathological processing of tau. These findings suggest that cortical Lewy body dementia has an aetiopathogenesis that is distinct from AD. Furthermore, APO E polymorphisms influence the development of dementia in both AD and cortical, but not subcortical Lewy body disease by mechanisms(s) that remain to be identified.

Summary

The pathology of Parkinson's disease (PD) is characterized by the presence of neuronal loss, Lewy bodies (LBs), and Lewy neurites (LNs) at predilection sites in the nervous system. During the course of PD a characteristic pattern of lesions develops in both the central and peripheral nervous system, with a predominant involvement of ‘efferent’ subcortical structures such as the substantia nigra and amygdala. ‘Afferent’ cortical structures such as the entorhinal region are frequently involved in Alzheimer-type pathology. In this chapter the clinical features and postmortem findings of 33 patients with PD are reviewed and compared, with special attention being paid to the frequent but not exclusive association of LBs/LNs with Alzheimer-type pathology. Although a clear relationship between the neuropathological findings and the clinical features of psychopathology and/or dementia could not be observed, one could speculate that the Parkinson-specific lesions in cortical and subcortical structures and the Alzheimer-type pathology, which is seen most often in the entorhinal region, reinforce each other and thus are responsible for the development of dementia in PD. CA2 ubiquitin-immunoreactive neurites were found in almost all patients with PD and should be considered a normal finding in PD, irrespective of whether or not the patient is demented.

Introduction

Thirty-three patients with a clinical history of Parkinson's disease (PD), with or without concomitant affective, behavioral, and/or cognitive changes were assessed. They were referred to the Department of Neurology of the Medisch Spectrum Twente, The Netherlands, to determine the relationship, if any, between clinical PD with or without dementia and neuropathological changes.

Summary

The pathological correlate of parkinsonism and dementia (PD-dementia) may be diffuse Lewy body disease (DLBD), Alzheimer's disease (AD) or a combination of both pathologies. Positron emission tomography (PET) studies show a resting pattern of fronto-temporo-parietal hypometabolism in both AD and in PD-dementia patients. Diagnostic criteria have been recently devised to try and distinguish between AD and dementia of the Lewy body type. We have studied three PD-dementia patients fulfilling the clinical criteria for DLBD with 18F-fluorodeoxyglucose (FDG) PET. The results showed an AD pattern of fronto-temporo-parietal hypometabolism, although these patients had only mild cognitive dysfunction. These preliminary results suggest that metabolic PET studies are unable to distinguish the cortical deficit of PD-dementia from AD, though the PD-dementia patients may have relatively greater frontal hypometabolism. Further studies with postmortem confirmation will be required to establish whether DLBD is associated with a distinctive pattern of resting hypometabolism.

Introduction

Patients with postmortem evidence of diffuse Lewy body disease (DLBD) present clinically with either isolated parkinsonism, dementia or a combination of both (PD-dementia). PD-dementia may also be a manifestation of patients who show isolated Alzheimer's (AD) type changes at postmortem, or a mixture of both Alzheimer and Lewy body pathologies.

Initially, Lewy body disease was categorized according to its distribution in the central nervous system, diffuse (DLBD), transitional and iso-lated brainstem subtypes being recognized (Kosaka et al., 1984). Antiubiquitin staining however, has shown that cortical Lewy bodies are present in nearly all patients with clinically typical Parkinson's disease (PD) (Perry et al., 1991; Schmidt et al., 1991; Hughes et al., 1993).

Summary

The concept of heterogeneity of Alzheimer's disease is based on molecular, neuropathological, clinical and neuropsychological features. An additional expression of possible heterogeneity has been revealed by the observation that patients affected by Alzheimer's disease differ in their response to pharmacologic interventions. This finding is stimulating a new experimental approach aimed at correlating neurochemical-neuropathological dysfunctions with the capability of selective drugs to improve specific ‘areas’ of cognition. The pharmacologic approach may thus serve as a tool to define specific subgroups of patients differentially responsive to a given therapy and, at the same time, to define new nosographic entities. Recent investigations evaluating the therapeutic potential of cholinesterase inhibitors have disclosed the existence of at least two subsets of demented patients defined as responders and nonresponders to the ‘cholinergic therapy’. The cluster of ‘responders’ to the cholinesterase inhibitors might include a significant number of subjects with a particularly severe dysfunction of the cholinergic system. The prominent vulnerability of the cholinergic system in the Lewy body dementia indirectly suggests that pharmacological treatments directly or indirectly enhancing cholinergic transmission might ameliorate some of the impaired cognitive functions.

The cholinergic deficit in degenerative dementia

Research on Alzheimer's disease (AD) over the past two decades has emphasized the dysfunctions of the basal forebrain cholinergic system. Drachman and Leavitt (1974) reported that anticholinergic drugs produce an acute state of cognitive impairment similar to the memory deficit observed in patients with AD. Accordingly, a direct relationship between the cholinergic system and AD was originally hypothesized.

Summary

Several aspects of movement control by neuronal pathways in the basal ganglia are summarized. Evidence from neurochemical analyses in various neurodegenerative disorders is presented to demonstrate that a severe loss of dopamine in the putamen does not of itself represent a necessary condition for the appearance of extrapyramidal symptoms, and that the appearance of extrapyramidal symptoms or sensitivity to antipsychotics eliciting extrapyramidal symptoms is not solely dependent on a lack of striatal dopamine. The strategies of reduction of cholinergic activity and of reduction of the firing rate of the serotonergic neurons are alternatives to the traditional dopamine replacement therapy in the management of extrapyramidal symptoms. Inhibition of dopaminergic activity by dopamine D2 receptor blockers, as a means of controlling psychotic symptoms is considered inappropriate in disorders such as Lewy body dementia with a potential for increased sensitivity to such medication.

Introduction

The major extrapyramidal features of resting tremor, cogwheel rigidity, akinesia and disturbance of posture are most commonly regarded as clinical symptoms of Parkinson's disease (PD), and neurochemically are associated with lesions of the dopaminergic projections to the corpus striatum from the zona compacta of the substantia nigra. However, these abnormal motor movements also occur in Lewy body dementia (LBD) and in other categories of patients, examples of which are listed in Table 34.1.

In considering these disorders, the questions under discussion are whether extrapyramidal features are always a result of loss of dopaminergic neurotransmission and, if not, what neurochemical environment is responsible for the absence or presence of parkinsonian symptoms in patients with variable losses of nigrostriatal dopaminergic function.

Summary

Information regarding non-cognitive symptoms in patients with senile dementia of Lewy body type (SDLT) was abstracted from a number of sources including postmortem, clinical and prospective studies. Psychotic symptoms occur in more than 80% of patients with SDLT. Visual hallucinations are especially common. Visual hallucinations, auditory hallucinations and delusional misidentification occur significantly more often in SDLT than Alzheimer's disease. Major depression occurs in 15% of patients with SDLT and Alzheimer's disease. Falls are common in SDLT occurring in 50% or more of patients, but not all studies find them to be significantly more common in SDLT than Alzheimer's disease. Little is known about the association of psychotic symptoms, depression or falls in SDLT and no effective treatment strategies are established.

Other important symptoms such as anxiety, aggression, wandering and inappropriate sexual activity have not been systematically studied.

Introduction

It is necessary to set the scene by considering the prevalence rates and the importance of noncognitive features in patients with Alzheimer's disease as there is only rudimentary information available concerning these symptoms in Lewy body dementia (LBD). Fifteen to 30% of patients with Alzheimer's disease in contact with clinical services suffer from concurrent depression and the prevalence rate of psychotic symptoms in clinical samples exceeds 60%. Psychotic symptoms cause distress to carers and to the patients themselves. They reduce the likelihood of people continuing to live in their own homes (Steele et al., 1990), are associated with increased family discord and there is accumulating evidence to suggest that the presence of psychotic symptoms predicts a more rapid rate of cognitive decline (Rosen & Zubenko, 1991).

Summary

There have been a number of reports detailing the occurrence of pathology sufficient for the diagnosis of Alzheimer's disease and Lewy body dementia in the same patient, leading to the term ‘Lewy body variant of Alzheimer's disease’ (LBV). The data available emphasize the difficulty in differentiating patients with pure Alzheimer's disease from those with the Lewy body variant but clinical features such as extrapyramidal signs or psychotic phenomena may be helpful. Patients with LBV can present with progressive memory loss and so, at least in the early stages of the disease, they are indistinguishable from patients with pure Alzheimer's disease and it is likely that such patients will be found in groups of patients with Alzheimer's disease. Generally, neuropsychological tests are disappointing in differentiating the two groups although there is a suggestion that frontal lobe dysfunction (as evidenced by atrophy on Computed Tomography scanning and neuropsychological tests) is more common in patients with Lewy bodies than those without. It is traditional to view such a clinical dilemma in terms of a spectrum disorder. One would postulate that the presence of Lewy bodies along with Alzheimer's disease pathology edges patients towards a presentation more clearly associated with diffuse Lewy body disease (confusional states, psychotic features, extrapyramidal signs). This is confirmed by clinical observations and supported by biological marker studies (such as apolipoprotein e4) in which patients with Lewy bodies take up an intermediate position between pure Lewy body disease and pure Alzheimer's disease. The exact contribution of Lewy bodies to the clinical syndrome of dementia needs to be more fully evaluated.

The history of dementia associated with Lewy bodies (DLB) began not long after the history of Alzheimer's disease. Alois Alzheimer described neurofibrillary tangles in a case of presenile dementia in 1907 and Friederich Lewy first described cytoplasmic inclusions in neurons of the substantia innominata in cases of parkinsonism in 1912. In 1923, Friederich Lewy published a monograph containing neurological, psychiatric, and neuropathological data on 43 patients with parkinsonism amongst whom 21 were demented (see also Forstl & Levy, 1991). Dementia associated with Lewy bodies was later described by Hassler (Hassler, 1938) and over two decades later in 1962, Woodard (see also Woodard, 1985) reported a series of psychiatric cases in which Lewy bodies were identified at autopsy – he called these cases of “Lewy body disease”. An isolated case was also reported in 1961 by Okazaki (Okazaki et al., 1961). Then in the early 1970s, the concept of ‘incidental Lewy body disease’ arose from the findings of Forno (1969) on long-stay psychiatric patients – cases that in retrospect most likely included cases of DLB. Dating from 1976, Japanese neuropathologists including Kosaka (see Kosaka, 1990) were responsible for describing the detailed clinical and pathological features of demented patients with cortical Lewy bodies which they termed ‘Diffuse Lewy body disease’ and divided into subgroups such as cortical type or brainstem type, based on the distribution of Lewy bodies and clinical presentation primarily with dementia or parkinsonism.

From the late 1980s onwards several groups raised the profile of this form of dementia by suggesting that it may be more common than previously suspected.