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The World Health Organisation uses the ICD-10 diagnostic and classification tool to list the features common in dementia. The diagnosis of the severity of the disease is produced by assessing the neurocognitive decline and the behavioural impact of the symptoms. Early evidence of the onset of dementia includes evidence of a decline in the general processing of information, with especial regard to memory. This memory dysfunction effects the acquisition of newly learned or previously learned information. Other trait characteristics include a decline in general cognitive abilities including deterioration in judgement and thinking processes, executive functions, language and attention (Petersen et al., 2000; Albert et al., 2001)
Clinical diagnosis is assessed through the discourse of a patient's history accompanied by cognitive and neuropsychological testing. Diagnosis of dementia requires the presence of symptoms for a minimum duration of six months. This is necessary to avoid confusing the symptoms with reversible identical temporary states such as in minor acquired brain injury. The severity of dementia is established by assessing the impact of the symptoms on the individual's daily life. A general diagnosis of the strength of the dementia is ascertained by defining the subcomponent factors related to the disease, memory reduction and cognitive dysfunction.
Mild memory loss refers to a reduced ability to recall newly learning information. This type of memory deficit is strong enough to hinder daily activities but does not impair independent living. Mild cognitive dysfunction impairs the individual from completing tasks otherwise capable of undertaking. The comorbidity between memory reduction and the loss of cognitive functions are descriptively related to the disease, but the correlation strength and direction of the deficits are unrelated. Individuals exhibiting mild memory loss can conversely show moderately high cognitive dysfunction and vice versa. In this case the diagnosis would be of moderate dementia. The clinical diagnosis of the strength of the dementia would be associated with either the amount and type of memory reduction or the level of cognitive decline, whichever is the greater.
Moderate memory deficit would relate to the extent that only highly learned and familiar information is retained. Moderate cognitive reduction would mean that daily activities might be increasingly restricted and poorly sustained. A diagnosis would suggest that an individual's daily life would be affected to the point that independent living would be difficult due to the extent of the memory and/or cognitive impairment.
A severe dementia would prevent the individual remembering any new information and only fragmented information from the past would be recalled. Severe cognitive dysfunction refers to an absence, or virtual absence, of intelligible ideation (World Health Organization, 1993). The individual would fail to recognise even close family members and/or formulate coherent thoughts. Due to the extent of the impairments, the prognosis of independent living would be almost impossible.
Other factors may include a decline in affective control, motivation, or a change in social behaviour (World Health Organization, 1993).
AD can elucidate other symptoms producing delusional, depressive, or hallucinatory states which can be independently defined or in combination, producing mixed symptomologies (Cummings, 2003; Lyketsos et al., 2002).
A diagnosis of AD entails recognising the features relating to dementia, memory and cognitive deficit, but also 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. Taking this into consideration AD diagnosis assesses factors relating to the stage of onset of the disease and the symptoms provoked. Defining early or late onset and atypical, mixed or unspecified dementia associated with AD (World Health Organization, 1993).
When the process of dementia begins prior to 65 years old, the designation of pre-senile dementia is prescribed. If the dementia is ascertained after 65 years of age the term senile is used. The disease is basically the same; however, the earliest changes are found in those memory functions mediated by the hippocampus and entorhinal cortex (Gómez-Isla, Price, McKeel, Morris, Growdon, and Hyman, 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).
The neuropathology associated with AD is distinct resulting from pathologies related to dysfunction and death of specific neurons (Price, Tanzi, Borchelt, Sisodia, 1998b). The degree of neurological dysfunction relating to the pathology of AD can be explained with respect to the structural atrophy on the macro and micro level. Research has looked at the functional changes relating to the neuropathology of the condition in context with the neuro-anatomical damaged associated with the condition.
On a microbiological level there appears to be a loss of large pyramidal neurons.................................., loss of neurons in certain subcortical neurons that project to the cerebral cortex....................................... 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 fibers 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...........................
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 et al., 1990). It has been shown that a reduction in NGF correlates with nerve death in AD (Hefti and Weiner, 1986).
On a structural macro 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, Lehtovirta, M.,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 has also been mentioned in the progression of AD. Gomez-Isla and Price et al., (1996) suggest that the entorhinal cortex 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 and it is severely affected in AD and is one of the first regions to be affected by AD. The entorhinal cortex is also known as Brodman's area 28. This area is important in all aspects of memory formation and recall. It is especially important in spacial memory and mediates impulses from the eyes and ears. This area is extensively interconnected with the higher association cortex. Cognitive disturbances relating to spacial awareness and the inability to process coherent information about the environment are illustrative of AD sufferers. A key factor of the early onset of the disease relates to moments of confusion which may be related to disturbances in the Brodman's area 28.
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 (Whitehouse et al., 1981), contributing to cognitive decline (Coyle, Price, DeLong, 1983).
At the final stage of the disease there is atrophy of the cerebral cortex involving the prefrontal, parietal, and temporal limbic system. 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 (Jack, et al., 2000)
The neurocognitive effects associated with AD relate to a reducing in memory function and a progressive deterioration of high order cognitive tasks such as with judgement and thinking executive functions, language and attention. Other factors relates to affective and behavioural changes. Researchers have explained these progressive changes in terms of neurochemical imbalances and toxicities, incorporating disruption to the anatomical structure and function of the brain.
Characteristic of AD symptoms have been explained by means of an imbalance in neural acetylcholine levels as suggested by Beeri, Andres and Lev-Lehman et al, (1995). A reduction in Nerve Growth Factors leading to neuron death, as prescribed by Lad, Neet, Mufson, (2003). Progressive cognitive dysfunction and memory impairments attributed to the loss of dendritic spines of pyramidal hippocampal region in AD, as stated by Lee, Moussa, Lee, Sung et al., (2010). And, or as Von Berhardi, (2007) suggest AD is partly due to the inflammation of microglial cells.
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, characteristic of Alzheimer's disease. This is associated with structural changes and subsequent cell death in acetylcholine producing neurons, progressively damaging cholinergic neurotransmission. In order to explore the molecular aspects of memory deficiencies associated with impaired 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 that produced the excessive AChE which caused the imbalance, also 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 previously mentioned in humans, 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. This localisation could explain the eccentricity of some symptoms such as emotional disturbances. The localised effects in these neural systems such as in parts of the limbic system could produce a globalised effect. This would explain the generality of the progressive cognitive impairment as more structures become involved in the progression of the disease.
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 recent results suggest that cognitive deficits in early AD were not associated with a cholinergic deficit. This would imply that cognitive deficits in AD may involve brain changes other than simply cholinergic system dysfunction. But that indicate an early defect in NGF receptor expression in 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 challenge in the area of neurotrophin therapy is delivery of these factors within the CNS. Another point of contention with this possible therapeutic procedure, relates to the size of NGF's themselves, they are two large to pass through the blood brain barrier and therefore intravenous or biomedical delivery would be worthless unless injected directly into the brain region. The most site specific method to date for delivery of NGF to basil forebrain neurons is via gene therapy and 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, due to socio-political and research constraints.
The hippocampal region of the limbic system has been of critical importance in the understanding of the different factors relating to memory. Much research has linked the amygdale with emotions and the hippocampal regions with that of memory function. Both structures also cooperate in many cognitive functions as would be expected. In AD there are symptoms related to cognitive and affective dysfunction specifically related to these brain regions. The pyramidal cells are the principal cells of the hippocampus. Bilateral damage to the hippocampus produces a marked impairment of the ability to form new associations, an inability to establish new memories at a time when remote memory is not affected. It is known that the loss of dendritic spines of pyramidal neurons is a factor in AD. This would produce a significant impairment for the hippocampal region to communicate with other brain regions.
Lee, Moussa, Lee, Sung 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 induced by beta-amyloid is thought to be 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 wild-type littermates. Furthermore the researcher discovered that over-expression of APP increased spine number and that APP levels 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 volume of specific brain regions (hippocampus, entorhinal cortex, and amygdala) involved in learning, memory, and emotional behaviours is reduced in AD patients. This decrease in size could be due to neuron death through ineffective synaptic connectivity resulting from reduced levels of APP and 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 several neurodegenerative diseases, including 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. The more behavioural demanding an individual is the more resentful caregivers can become. Furthermore increased medication to reduce the negative behaviour effects of the specific condition can make the prognosis worse for the individual. Medication for AD can be a cause of some of the behavioural effects. Side effects from prescription medications may be at work. Drug interactions may occur when taking multiple medications for several conditions. Additional medication for other illnesses that may exist in tandem with AD can also produce unknown behavioural side effects.
Other more subtle influences may elicit a behavioural response such as anxiety or aggression is the environmental effect of being moved into residential care. Fear and confusion which are symptomatic of AD can produce secondary behavioural response such as frustration and stress, to both the individual and the caregivers.
In essence 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 effects of AD in terms of social factors are far reaching with the extent of the prevalence of the disease in an aging population. 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. Alzheimer's disease is the most common degenerative disorder of the central nervous system in the elderly. Alzheimer's disease accounts for at least 55% of all cases of dementia (Alzheimer's Association of America, 2010). It directly affects 5.3 million in American and by 2050 the number of individuals with the disease may reach 16 million in the USA alone. The worldwide prevalence rate of individual is circa 26.6 million (Alzheimer's Association of America, 2010).
Millions of individuals will require care, putting pressure on families and the resources of institutions.
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 in managing AD symptoms. 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 on the neurosystem. 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. This part of the treatment reduces the anguish that the individual and family caregivers may experience. If the individual is in a private care facility it allows proper management of the individual welfare.
Unfortunately, pharmaceutical and biotech companies have limited their efforts in neuro-therapeutics development because of the high rate of failure and costs in clinical testing of drug candidates for these disorders (Lee et al., 1999).
In Alzheimer's disease like Parkinson's disease growing evidence has indicated that an associated with 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 new medicines aimed at reducing this inflammatory effect of the disease on neurons and this could reduce or slow the symptomology of AD (Etminan et al., 2003).
Gene therapies can also in the future offer a positive prognosis of reducing or slowing the effects of the disease. Recently, much progress has been made in the localisation of genes associated with neurologic diseases, including Alzheimer's, Huntington's, and Parkinson's Disease. The goal of gene therapy is to replace a mutated or deleted gene. In disorders such as AD, gene therapy can be used as a tool to deliver therapeutic substances. The discovery of the class of neural protective substances called NGF's offers the potential for the first time to reduce cell loss in neurological disease and to stimulate the function of remaining neurons (Lad, et al., 2003). Utilising gene delivered NGF to the nervous system may prevent cell death and stimulate cell function. 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 et al., 2000).