ON THE ROAD TO THERAPEUTICS: BIOLOGICAL MECHANISMS OF PARKINSON'S DISEASE AND ALZHEIMER'S DISEASE

This paper has sought to explore and summarise more recent findings on the genetic underpinnings of Parkinson's disease (AD) and Alzheimer's disease (AD). Recent studies have contributed to our understanding of these two devastating diseases. As the most common neurodegenerative disease, AD accounts for about two thirds of cases of dementia – ranging in various studies from 42 to 81 per cent of all dementia – with vascular causes and other neurodegenerative diseases such as Pick's disease and diffuse Lewy-body disease constituting the majority of the remaining cases. Meanwhile, it has been identified that PD is the second most common neurodegenerative disorder, after AD. The cause of PD remains unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex. In light of the current findings and issues on PD and AD, this paper highlights the range of therapies available for those afflicted with these diseases.


INTRODUCTION
The news is full of reports about dementia and its devastating effects. For instance, it has been reported last March of the previous year that rates of dementia in the Isle of Man is on the rise (BBC, 2014). When asked, most people have a particular fear of losing their mental faculties to dementia, over and above falling victim to other agerelated conditions. Dementia is therefore a condition that everyone can relate to -particularly in the light of There are several kinds of neurodegenerative disorders such as (PD), (AD), Huntington's disease, and motor neuron disease (also known as Amyotrophic lateral sclerosis). However, this paper aims to discuss the contrasting and comparing the biological pathology and underlying causes of PD and AD.
· What are the available treatments?

Who Gets Afflicted?
Both PD and AD disorders are prevalent among the elderly.
Neurons play an important role in the development of PD.
Those neurons that are crucially involved in PD are associated with the substantia nigra, a structure situated in the midbrain. This structure is mainly responsible for movement and coordination. A recent study (Reeve, Simcox, & Turnbull, 2014) has demonstrated that in PD, the dopaminergic neurons of the substantia nigra increased the risk with advancing age. Aside from those damages, it has also been observed that there is a substantial decline in vital processes for the function of substantia nigra neurons, dopamine metabolism, wild type mitochondrial DNA copy number, and protein.
The substantia nigra is the part of the brain that is responsible for movement, addiction and reward (Rabey & Hefti, 1990). The decline in the function of the substantia nigra is often characterised by stiffness, tremor, bradykinesia and akinesia which are the most common symptoms of PD (Jankovic, 2008) .
By contrast AD is associated with increasing deposits of amyloid-beta (Aβ or A beta) -which are amino acids -in the brains of sufferers. These amino acids are thought of as the major component of the amyloid plaques observed in the brains of patients suffering with AD. A recent study on AD (Kövari, Herrmann, Bouras, & Gold, 2014) has indicated that amyloid deposition is increasing in ageing brains.
Amyloid plaques associated with AD are thought to impair functions by inhibiting the electrical conductivity and the action of acetylcholine in the neurons. Consequently the messages get slowed down or blocked.
What Triggers These Disorders?

Brain injury
In spite of what the previously mentioned studies suggest, neurodegenerative disorders -particularly PD and ADmay not be simply attributed to ageing. There are other factors that could also contribute to the development of having PD and AD. For instance, although such disorders are widespread to older people, there have been recent evidences (e.g. Gardner & Yaffe, 2014) that traumatic brain injury may increase the risk of early onset dementia.
One investigation (Marras et al., 2014) involving 65 cases of mild traumatic brain injury revealed that there may be an important causal relationship between brain injury and PD.
Meanwhile, it has been proven in another experiment on causative factors in AD (Sawmiller et al., 2014) that it was shown that traumatic brain injury in mice delivered through a gas-driven shock tube device, significantly increases bamyloid deposition glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines (chemicals which appears in large amounts in patients with AD).

Environmental factors
It is known that PD is characterised by the inability of the brain to produce enough "dopamine," a neurotransmitter that is responsible for mood and for regulating movement.
However, there are earlier findings that suggest a causal link with pesticides and other harmful environmental toxins (e.g., Greenamyre, 2000).
Recently, there are also increasing amount of evidence have explored the restless legs syndrome (RLS) and PD and ultimately they have found out that these two disorders can co-exist. Additionally, they have also explored whether or not these two disorders share a common pathophysiology.
It was one of their findings that as PD progresses, nocturnal disturbances become even more noticeable, in association not only with motor symptoms but as well as with non-motor symptoms.

Genetic predisposition
The main known risk factor for PD is age. However, research has identified susceptibility genes such as synuclein, l e u c i n e r i c h r e p e a t k i n a s e 2 ( L R R K-2 ) a n d glucocerebrosidase (GBA) which suggest that genetic predisposition is another essential causal factor. Meanwhile, the National Health Service (NHS), a publicly funded healthcare system in the UK describes AD as caused by regions of the brain wasting away, a process known as atrophy. Results to a multiplicity of damages in the structures of the brain. It is not known exactly what causes this process to begin, but people with AD have been observed to have unstable levels of amyloid plaques and tau tangles present in the brain. As a result, this reduces the effectiveness of healthy neurons, gradually damaging them. Over time, this loss spreads to other regions of the brain, including the grey matter, which is mainly responsible for processing thoughts as well as the hippocampus, which plays an important function in memory (NHS, 2012).

Diet
Studies looking at other potential factors that could trigger dementia are ongoing. Such findings are shedding further lights on our understanding of the nature of this disorder.
A recent study (Cai et al., 2013) reveals that advanced glycation end (AGE) food products affect the chemistry of the brain and consequently cognition. AGE is released through frying meat in pan, oven or grill. It is a byproduct when fats or proteins react with sugar, which happens during the cooking process. The result of this study is quite alarming as frying foods is a very common method of cooking.
The experiment involved feeding mice with AGE-based foods and the researchers found out that those mice that consumed low levels of AGE-based foods were able to prevent the building of damaged amyloid. On the contrary, when the levels of AGE have been increased the mice performed poorly in both thinking and physical tasks.
The study further discusses their observation among people over 60 that the decline in their cognitive abilities is linked with high levels of AGES in their diets.

Symptoms and Diagnoses
Symptoms of PD are mainly movement-related (e.g., AD is a specific diagnosis, named after Alois Alzheimer, a German psychiatrist who discovered it in 1906. AD is characterised by difficulty remembering events, confusion, aggression, and mood swings among others. In contrast, the blanket term dementia refers to a whole range of cognitive symptoms that have a range of possible causes. AD can be confirmed through a series of brain scans, cognitive-behavioural assessments, and autopsy. This loss has instead been more closely associated to a soluble form of beta-amyloid that can intervene with the production and release of acetylcholine, and disrupt the behavior of a chemical called nerve growth factor that is involved in maintaining the structure and function of cholinergic neurons. There is also evidence that suggests that damage can be caused by the immune system reaction to the initial production of fibrillar beta-amyloid, before plaque formation, that involves the release of harmful chemicals (Jack, et al., 2010).

Acetylcholine
The neurotransmitter acetylcholine is essential for judgement and learning but this is subsequently loss in AD.
Combination therapy (with the N-methyl-d-aspartate r e c e p t o r a n t a g o n i s t, m e m a n t i n e , a n d a n acetylcholinesterase inhibitor) can be used however for the treatment of AD (Parsons, Danysz, Dekundy, & Pulte, 2013).
In contrast, acetylcholine in PD is in stable supply but due to the decrease in dopamine and the slower response time, the homeostasis required for normal movement is disrupted. Acetylcholine acts as an excitator y neurotransmitter and causes the muscles to contract while dopamine sends the message to relax. However, this seemingly simple process does not take place in PD. The striatal dopaminergic system, which is especially at risk to neurodegeneration for this disorder, appears to be the key contributor to these motor problems. However, numerous other neurotransmitter systems in the striatum are most likely to also play a significant role, including the nicotinic cholinergic system (Quik, et al., 2009).

Clinical approach
Currently, there is no known cure for PD, but there are medical treatments available including occupational, surgical procedures, pharmaceuticals, physical therapy.
Although, the mainstay drug that is being used is still levodopa. By replacing dopamine, this drug can minimise the motor symptoms of the PD by replacing the dopamine.
Levodopa is frequently combined with a peripheral decarboxylase inhibitor such as carbidopa. These drugs help by disabling side effects such as dystonia, and immobile rigidity, dyskinesias, but may also have neuroprotective factors (Davie, 2008).
In contrast, drugs such as galantamine, donepezil, and rivastigmine (which are AChE inhibitors) can be prescribed for patients with mild to moderate symptoms of AD.
Memantine may also be prescribed for those with moderate AD who cannot take AChE inhibitors or for those patients suffering with severe Alzheimer's disease (NHS, 2012).

Discussion
The While it has been revealed that there were significant psychiatric differences between patients with AD and demented patients with PD, but neuropsychological differences were restricted to a single cognitive domain. The outward manifestations of growing older:grey hair, wrinkles, stiffening joints, slower response times and 'senior moments'are as well-known as the many products advertised to address them, researchers still remain to know little about how people age. Yet the incentive to uncover the secrets of ageing is powerful: advancing age is the single greatest risk factor for most human diseases, from arthritis and cancer to diabetes and neurodegenerative disorders.

Recommendations
To address the complex needs of the patient with There are a number of therapies for PD which seems to be effective at mitigating the worst symptoms of the condition but still not able to predict its onset or assess vulnerability, nor can prevent or cure the disease.
By contrast AD is harder to diagnose less about the underlying causes although recent studies has made a significant contribution to predicting who might be at risk and raised the possibility of considering prophylactic therapy. AD is harder to generally treat and mitigate, Like