The pathological lesions seen in the brain of those with AD are inevitably associated with dysfunctions of the neurotransmitter systems. Of these, deficits in the neocortical cholinergic system have been well established for over a decade but more recently changes in the concentrations of the neuropeptides somatostatin and corticotrophin releasing factor (CRF) have been added to the list. Deficits in the biogenic amines noradrenaline and serotonin have also been reported to occur but a significant decrement in their concentrations in the brains of patients with AD has not been consistently reported. Nevertheless, a functional deficit in such mono-amines may contribute to mood and other psychological changes which are often associated with the condition. In regard to the cholinergic deficit, a decrease in the synthesizing enzyme, choline acetyltransferase, and the degradative enzyme acetylcholinesterase, would appear to play a key role. Such abnormalities have therefore become the most important neurotrans-mitter markers of AD. A compensatory increase in the activity of the choline transporter has also been reported, which presumably occurs in an attempt to compensate for the deficit in the cholinergic function.
It was following the identification of the cell loss in the nucleus basalis of Meynert, from which the cortical and limbic regions receive their cholinergic inputs, together with the demonstration that the cholinergic system is involved in learning and memory, that the anticholinesterases were developed for the treatment of AD. However, it should not be overlooked that despite the presumed importance of the cholinergic deficit in the terminal stages of AD, there appears to be little change in this system in the mild to moderate stages of the disease.
Deficits in several neurotransmitters, in addition to somatostatin and CRF, have consistently been reported to occur in AD. In addition, the density of CRF receptors appears to be increased while those for somatostatin are either decreased or unchanged. The changes in both the brain and the CSF concentration of CRF would, unlike those in somatostatin, appear to occur relatively early in the disease and correlate with the severity of the condition. Such changes may be reflected in a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis that may play an important role in the pathology of AD.
Table 14.1. Changes in the neurotransmitters in the brain of an Alzheimer patient Neurotransmitter system Changes occurring in Alzheimer's disease
Dopaminergic system Serotonergic system
Decreased choline acetyltransferase and acetylcholinesterase activity in cortex. Reduced choline uptake and acetylcholine synthesis. Loss of cells in nucleus basalis and occurrence of tangles in remaining cells in the brain area Decreased dopamine beta-oxidase and reduced noradrenaline synthesis. Loss of cells in the locus coeruleus and occurrence of tangles in remaining cells Slight reduction in dopamine
Some reduction in 5-HT synthesis with a loss of cells in the raphe nuclei and the occurrences of tangles in remaining cells
Reduction in somatostatin and corticotrophin releasing factor immunoreactivity in cortex. No convincing evidence of change in the concentration of substance P, enkephalins, cholecystokinin, neuropeptide Y, glutamate, aspartate or GABA
There has been considerable interest in the involvement of the major neurotransmitters in the possible aetiology of Alzheimer's disease. Thus it is well established that the nucleus basalis of Meynert and related areas of the basal forebrain show a distinct loss of cholinergic cell bodies in patients with Alzheimer's disease. Similarly, serotonergic neurons of the midbrain raphe area and noradrenergic neurons of the locus coeruleus have been shown to be significantly diminished, particularly in early onset Alzheimer's disease. A summary of the pathological changes in the neurotransmitter systems in the brain of the Alzheimer patient is given in Table 14.1.
The finding that a gross deficit occurs in central cholinergic transmission in Alzheimer's disease, the degree of dementia being correlated with the relative deficit in central cholinergic transmission, has led to the suggestion that this is the primary cause of the dementia of Alzheimer's disease. However, it is now increasingly accepted that a cholinergic deficit is unlikely to be the only or indeed a major causative factor. Thus not all patients with the disease, and showing the typical neuropathological changes, show a reduction in the activity of choline acetyltransferase, the enzyme concerned in the synthesis of acetylcholine. Additionally, other patients show normal cholinergic cell numbers in the nucleus basalis of Meynert. More recently it has been shown that patients with a rare neurological disorder, olivopontocerebellar atrophy, exhibit a gross loss of cholinergic neurons in the basal forebrain and yet show no signs of dementia.
It might also be argued that if Alzheimer's disease was primarily due to a cholinergic deficit, it should be possible to correct the deficit by suitable centrally acting cholinomimetic drugs. Despite the numerous studies in which different types of cholinomimetic drugs have been administered, there is no overwhelming evidence to suggest that these drugs have any substantial benefit to the patient (see below). Thus it would appear that, despite the widely confirmed findings that various ''classical'', peptide and amino acid neurotransmitters are defective in Alzheimer's disease, it is debatable whether a defect in one specific neurotransmitter system is responsible for the clinical signs and symptoms of the disease. There is also some debate about whether the site of the lesion is primarily cortical or subcortical.
The involvement of the excitatory amino acid neurotransmitters, particularly glutamate, in post-stroke epilepsy and possibly multi-infarct dementia has led to the suggestion that they may also be involved in the aetiology of Alzheimer's disease. Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons. In the hippocampus, glutamate has been implicated in memory; it is widely believed that its ability to elicit long-term potentiation is of fundamental importance in memory formation. One of the major excitatory amino acid receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor. Antagonists of the NMDA receptor block the action of glutamate and impair spatial discrimination learning in animals and also memory formation. A disruption in the pre- and postsynaptic excitatory amino acid pathways has been found in patients with Alzheimer's disease. It has been suggested that initial hyperactivity of the glutaminergic input to the hippocampus results in excessive hyperexcitability of the hippocampal cells, leading eventually to cell death.
The primary mechanism whereby glutamate can cause excessive cellular hyperactivity, and ultimately cell death, is via a loss of calcium homeostasis. Calcium ions serve as an intracellular signal that mediates the actions of neurotransmitters and growth factors. The increase in intracellular free calcium is normally transient and is rapidly restored to resting levels by membrane extrusion mechanisms and calcium-binding proteins such as calmodulin. Sustained increases in intracellular calcium, as could occur following excessive glutamate release, result in cytoskeletal disruption, axonal degeneration and cell death.
In addition to glutamate, various growth factors and amyloid have also been shown to destabilize the intracellular calcium concentration and to induce neurofibrillary-like degeneration in cultured brain cells. An attractive feature of the calcium hypothesis of Alzheimer's disease is that it helps to explain the heterogeneity of the disorder. In addition to functional abnormalities in excitatory amino acids, growth factors, amyloid protein, etc., calcium channels and binding proteins may also be involved. It is not without interest that various dietary and environmental factors (such as aluminium) may also contribute to the calcium defect, so leading to the disorder.
It should be emphasized, however, that not all investigators agree that the degenerative changes in cortical neurons are due to glutamate excitotoxi-city. Thus, three groups of British and Swedish investigators have suggested that the glutaminergic system is hypoactive rather than hyperactive in Alzheimer's disease. Nevertheless, the development of drugs that block NMDA receptors may be of value in the treatment of multi-infarct dementia, in which there is evidence that excessive glutamate release, with the consequent neuron degeneration, follows the cerebral hypoxia.
It may be concluded that it is not possible at present to identify any one neurotransmitter system as being of primary importance in any of the dementias and that the recorded neurochemical changes are possibly secondary to more fundamental disturbances, the nature of which is unclear. Nevertheless, significant correlations have been shown to exist between neurotransmitter disturbances and behavioural symptoms which may be of value in formulating treatment strategies.
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