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The definition of dementia refers to progressive impairments of previously intact mental faculties. The most prevalent cause of progressive impairment in the elderly is Alzheimer's disease (AD). AD is described as a subtype of dementia that exhibits a progressive neurological disease characterised by memory loss, behavioural changes, and global functional impairment in activities of daily living (McKhann, Drachman, Folstein, et al., 1984).
The World Health Organisation uses the ICD-10 diagnostic and classification tool to list the features common in dementia. Early evidence of the onset of dementia includes evidence of a decline in the general processing of information, with especial regard to memory. And a decline in general cognitive abilities including deterioration in judgement and thinking processes, executive functions, language and attention (Petersen, Jack, Xu, et al,, 2000; Albert, Moss, Tanzi, et al, 2001).
A diagnosis of the strength of the dementia is associated with the level of memory reduction and/or cognitive decline, whichever is the greater. Other factors may include a decline in affective control, motivation, or a change in social behaviour (World Health Organization, 1993) and delusional, depressive, or hallucinatory states which can be independently defined or in combination, producing mixed symptomologies (Cummings, 2003; Lyketsos, Lopez, Jones, et al, 2002).
A diagnosis of AD entails excluding the possibility of misdiagnosis with other disorders associated with dementia, such as cerebrovascular disease, Parkinson's disease, Huntington's disease and normal pressure hydrocephalus. Other causes of similar effects relating to AD may include a systemic disorder such as hypothyroidism and vitamin B12 or folic acid deficiency, hypercalcaemia. Even alcohol or drug abuse may elicit similar dementia type effects (World Health Organization, 1993).
Different symptoms associated with dementia may be related to variance within the disease itself. This may suggest an existence of various sub-types of the condition. (World Health Organization, 1993).
The earliest changes are found in those memory functions mediated by the hippocampus and entorhinal cortex (Gómez-Isla, Price, McKeel, et al, 1996).
Other common types of degenerative personality and behaviour are generally well preserved. As the disease progresses, these functions and, eventually, motor functions are also affected (Beeri, Andres, Lev-Lehman et al, 1995). A common feature in AD's pathology involves increased regionalised neuronal mortality and an accumulation of intraneuronal and extracellular filaments termed neurofibrillar tangles and senile plaques, respectively (Smith, 1998; Price, Tanzi, Borchelt, et al, 1998b). The pathology in AD can be explained with respect to the structural atrophy on the local and global level.
On a microbiological level there appears to be a loss of large pyramidal neurons (Bozzali, Falini, Franceschi,et al 2002), loss of dendritic spines of pyramidal neurons in the involved cortex (Lee, Moussa, Lee, Sung et al., 2010). There appears to be an increased amount of plaques and tangles within the neural system. Tangles are twisted fibres of another protein called tau that builds up inside cells. Research has show that a major feature of AD involves these neurofibrillary tangles which have insoluble tau proteins that form aggregates. These large aggregates form the tangles that can be physical barriers to transport which might interfere with normal neural functioning. Plaques are deposits of a protein fragments called beta-amyloid that builds up in the spaces between nerve cells. These extracellular plaques contain insoluble fibrils of beta amyloid protein. Plaques may act similarly in creating neural blockages as with neurofibrillar tangles but also add an element of toxicity to the mix, contributing to additional nerve death (Giulian, Haverkamp, Li, et al 1995).
With respect to neurochemical aspects of AD there appears to be a link between a reduction in acetylcholine and a decrease in the acetylcholine synthesising enzyme choline acetyltransferase in the cerebral cortex (Wilcock, Esiri, Bowen, Smith, 1982). Nerve Growth Factors (NGF) that are produced throughout the brain are believed to support the integrity of cholinergic systems (Sofroniew, Dunnett, Isacson, 1990). It has been shown that a reduction in NGF correlates with nerve death in AD (Hefti, Weiner, 1986).
On a structural local level there is significant correlation in Alzheimer's disease between the degree of atrophy of the hippocampus and the presence of dementia (Laakso, Soininen, Partanen, et al.,1998). There have been many studies suggesting a reduction in size of the hippocampus in AD and dementia. Milner (1972) had shown that bilateral removal or damage of the hippocampus produces great difficulty in learning new information, a condition called anterograde amnesia, which is a key feature of AD. The amygdala has also been implicated with the dysfunctions associated with AD. Wright and Dickerson et al (2007) showed that amygdala activity correlated with the severity of irritability and agitation symptoms in AD. Lesions of the amygdala produce alteration of emotional response but might not always impair memory.
The entorhinal cortex also known as Brodman's area 28, has also been mentioned in the progression of AD. Gomez-Isla et al., (1996) suggest that the B. area 28 plays a crucial role as an intermediary structure connecting the neocortex and the hippocampal formation. It also acts as an excitory mechanism for the hippocampus is one of the first regions to be severely affected by AD. This area is extensively interconnected with the higher association cortex and is especially important in spacial memory.
The Nucleus Accumbens receives connections from the amygdala and from the basal ganglia and thus provides a major link between the limbic and basal nuclei. In AD, there is a significant loss of cholinergic neurons in this nucleus. Cholinergic neurons of the basal forebrain undergo profound atrophy and death during the course of AD contributing to cognitive decline (Coyle, Price, DeLong, 1983). There is evidence of decreased regional blood flow in the parietal and temporal lobes with involvement of other cortical areas at the later stages of AD (Matsuda, 2001).
The neurocognitive effects associated with AD relate to a reducing in memory function and a progressive deterioration of high order cognition Researchers have explained these progressive changes in terms of neurochemical imbalances and toxicities, incorporating disruption to the anatomical structure and function of the brain.
Beeri, Andres and Lev-Lehman et al, (1995) suggest that neuro-chemical aspects of AD involving acetylcholine (AChE) are responsible for the progressive cognitive deterioration. This is associated with structural changes and subsequent cell death in acetylcholine producing neurons, progressively damaging cholinergic neurotransmission. The experimenters created transgenic mice that produced human AChE in brain neurons. The transgenic mice had double the AChE enzyme levels than the control mice. The transgenic mice displayed an age-independent resistance to the hypothermic effects of the AChE inhibitor, but also to secondary resistances to muscarinic, nicotinic and serotonergic agonists. At six months of age, the transgenic mice developed progressive learning and memory impairments losing abilities to respond to training in a spatial learning water maze test.
The transgenic mice however performed normally in the same test at four weeks. The researchers conclude that upsetting cholinergic balance maybe the cause of progressive memory decline as seen in Alzheimer's disease. This research if applicable to humans could provide insights to a possible biomedical solution to reducing the cognitive deterioration associated with AD, by normalising the levels of AChE in areas such as the nucleus accumbens, basal ganglia and the cerebral cortex.
However the researcher also stated that the transgenic mice demonstrated dissociation between this imbalance and beta-amyloid deposits. This could imply that cholinergic imbalance may lead to abnormal beta-amyloid expression. Further research is needed to explore the relationship between AChE imbalance, beta-amyloid production and secondary resistances to other agonist before any meaningful research can ascertain possible biomedical interventions based on these factors.
The severity and type of cognitive impairment initially expressed by individual AD sufferers may suggest which neural structures are being impaired by the disease. If there is an excessive localised build up of tangles or plaques causing blockages in neural communication, reduction in regional brains areas will produced different cognitive and behavioural effects. Also a reduction in the production or localised absorption of acetylcholine may elicit similar effects.
Lad, Neet, and Mufson, (2003) suggested that trends in the study of neurotrophic factors such as Nerve Growth Factors (NGF) could elicit real therapies for the treatment of AD. This premise was based on the observational research, mainly in rats, that the cholinergic neurons in the basal forebrain provide a major source of AChE for the cerebral cortex. And that the hippocampus undergoes a selective and severe degeneration in advanced AD.
This might suggest that these neurons are dependent upon NGF for survival. The researchers state that a reduction or imbalance in the uptake of these NGF is fundamental in neural dysfunction and that AD is a side effect of reduced levels of NGF reaching the neurons within key structures of the brain.
The researchers suggest by way of meta-analysis that cognitive deficits in AD may involve brain changes other than a cholinergic system disruption. An early defect in NGF receptor expression in the basal forebrain could offer a solution to the AChE imbalances. The researchers argue that interventions to facilitate NGF actions may reduce cholinergic nerve dysfunction in late stage AD, ultimately delaying the onset of severe cognitive deterioration.
However a major issue in the area of neurotrophin therapy is the delivery of these factors within the CNS. The relative size of the NGF's is too large to pass through the blood brain barrier so medicinal delivery would be worthless difficult. The most site specific method to date for delivery of NGF to basil forebrain neurons is via gene therapy but this methodology has ethical and political issues associated with its usage. This means that this therapy will be a long way from coming to fruition.
Lee, Moussa, Lee, et al., (2010) suggested that little is known of the amyloid precursor protein (APP). This protein is important in the formation of beta-amyloids. Much research however has been done on the role of beta-amyloids and cognition with respect to AD. Synapse loss due to beta-amyloid has been suggested as a primary source for cognitive decline in AD. The researcher showed in an in vivo experiment that cortical layers and hippocampal pyramidal neurons in 1 year-old APP-deficient mice had fewer and shorter dendritic spines than a control.
Furthermore the researchers discovered that over-expression of APP increased spine number and were tightly correlated with spine density, obeying a nearly perfect linear relationship, whereas under-expression of APP reduced spine density in cultured hippocampal neurons. The researchers stated that the reduced volume of specific brain regions (hippocampus, entorhinal cortex, and amygdala) could be due to neuron death through ineffective synaptic connectivity, due to the malformation and reduction in dendritic spines. This research suggests that the role of beta-amyloids and amyloid precursor protein is far from clear with regard to the role played in AD.
Rommy Von Berhardi, (2007) suggest that glial cells are the major producers of inflammatory in the neural substrate of the brain. The researcher also suggests that cytotoxic activation of glial cells is linked to neural degeneration in AD. The study suggests that microglial cell activation is enhanced under pro-inflammatory conditions, indicating that glial cell responses to beta amyloid related proteins can be a critically dependent component. The researcher also suggests that it is not clear if beta-amyloid aggregation is the cause of AD or just a consequence of other pathophysiological changes such as a pro-inflammatory environment. An accumulation of amyloids does not always constitute a senile plaque, without the inclusion of an inflammatory response.
Von Berhardi states that inflammations are fundamental in the progression of AD. These events result in increased processing of APP into beta-amyloid and altered interaction of beta-amyloid with glial cells, impairing its clearance and potentially creating a reactive inflammatory response. It is this reactive inflammation that creates the plaques evident in AD. However research has shown that AD does not respond to anti-inflammatory medication as well as in ought to if the symptoms were purely related to this response (Etminan, Gill, Samii, 2003).
For many people changes in a person's behaviour is the most distressing and difficult effect of the disease to deal with. Behavioural other than those immediately evident from cognitive deterioration and memory loss can include anxiety, depression, agitation, aggression and sleep disturbances and a complete loss of social interest and apathy. The behavioural effects can have direct effects on the level of care ascertained in a private or family environment. Medication for AD can be a cause of some of the behavioural effects. Side effects and drug interactions may occur when taking multiple medications for several conditions.
Behavioural responses are multi faceted and can be directly or indirectly related to the disease itself in a physical way or by the effects of living with the disease in a psychological sense.
There are neurological, biochemical, and genetic features relating to the susceptibility to the disease. The over 75yrs and 85yrs age groups are the fastest growing section of the western population because of this AD has been called the silent epidemic. AD accounts for at least 55% of all cases of dementia (Alzheimer's Association of America, 2010). It affects 5.3 million in American and by 2050 this may reach 16 million. There are 26.6 million individuals with AD worldwide (Alzheimer's Association of America, 2010).
Millions of individuals will require care, putting pressure on families and the resources of institutions.
Pharmaceutical and biotech companies have limited their efforts in neuro-therapeutics development because of the high rate of failure and costs in clinical drug testing (Lee et al., 1999). The prognosis for AD sufferers at present is relying on human gene research and new treatments. Biomedical interventions have had a mixed response with some individuals faring better than others. The strategy in medicating individual with AD is two pronged approach. Firstly it is designed to attempt to slow the onset of the degenerative effects of the disease. Secondly the medication is designed to allow the patient to be managed in a private or public setting, by way of reducing negative behavioural side effects of the condition.
In AD, growing evidence has indicated that an inflammatory response by activated microglial cells could be a factor in the severity of the symptoms (Von Berhardi, 2007). Further research in this area could produce better medicines aimed at reducing this inflammatory effect of the disease on neurons, if the desire is there from the large pharmaceutical companies (Etminan et al., 2003).
Recently, much progress has been made in the localisation of genes associated with neurologic diseases. The goal of gene therapy is to replace a mutated or deleted gene. In disorders such as AD, gene therapy can also be used as a tool to deliver therapeutic substances. Early research has shown that NGF delivered by gene therapy can prevent cholinergic neuronal mortality in rats (Mandel, 1999; Blesch, 2002) and to reverse age related cholinergic neuronal atrophy (Klein, Hirko, Meyers, et al., 2000). The future should be bright for AD therapies.