Pharmaceutical Science: Alzheimer's Disease - Coursework Example

ALZHEIMER'S DISEASE By Name Course Instructor Institution City/State Date Alzheimer's disease (AD) Introduction Alzheimer's disease (AD) was first discovered in late 1901 after Auguste was taken by Karl Deter (her husband) to a hospital that deals with epileptics and mental illness in Frankfurt, Germany. The name of the disease was coined from Dr. Alois Alzheimer; in 1906, he had noted that the brain tissue of the woman had some peculiar changes. Some of the symptoms before her death included unpredictable behaviour, language problems, as well as memory loss. After dying, her brain was examined by Dr. Alois Alzheimer who established tangled fibres’ bundles (currently recognised as tangles, tau or neurofibrillary) and some unusual clumps (nowadays referred as amyloid plaques) (Schmid, 2008). AD has an enormous effect not only to those diagnosed with it but also family members. For instance, the children or spouses of individuals with the disease become caregivers. As the disease progresses, the roles in the family start changing which could become very challenging for some family members. Statistically, the number of people living with AD is approximated to be around 44 million people, but just 25% of these people have been diagnosed (Alzheimers.net, 2017). The prevalence of the disease in Western Europe is exceedingly high while in the Sub-Saharan Africa is considered to be very low.  AD has been cited as one of the main cause of disabilities amongst the elderly people. In the U.S., $236 billion was spent in 2016 to care for AD patients while the global cost of both dementia and AD is approximately $605 billion (Alzheimer's Association, 2017). This is the same as 1 per cent of the total world’s GDP. Alzheimer's Association (2017) projects that the number of people aged above 65 years with AD in the U.S. are almost 10% and by 2031 over 3 million people aged 85 years and older will have AD. Currently, the number of Americans living with the disease is more than 5.3 million and it is projected that by 2050 the number of AD patients in the U.S. will stand at 16 million unless a cure is found. According to Alzheimers.net (2017), two thirds of people with AD are women and close to 30 per cent of people the disease suffer from diabetes and heart disease. Most of the existing studies such as Andrade and Radhakrishnan (2009) have established that the existing interventions range from pharmacological treatments to lifestyle measures. The current research on finding a cure and improving treatments focus on finding new ways of treating AD considering that the present drugs are used to reduce the disease symptoms and slow the disease progression. Section 1 Basically, AD normally progresses through some stages; early-stage (mild AD), middle-stage (moderate AD), as well as late-stage (severe AD). Given that the disease affects individuals differently, every individual would experience progress or symptoms all through the stages of AD differently. Patients with Mild AD can function without help. They can still work, drive and partake in different social activities. However, the person would likely experience memory lapses, like failure to remember familiar location or words. The friends, family and neighbours would start noticing some difficulties such as lack of concentration or uttering words. The moderate AD is considered to be the longest as compared to other stages and could last for some years. While AD progresses the patient would need an increased level of care. At this stage, the patient gets angry or frustrated easily and his/her behaviour start changing. When the brain’s neurons get damaged it becomes challenging for the people with AD to perform routine tasks and express thoughts. Some of the symptoms of moderate AD include poor memory, increased confusion, inability to control bladder and bowels, sulkiness, and many others. In the last stage, people with severe AD completely lose their environment response ability environment, cannot communicate effectively, and ultimately, they lose their movement ability. Their cognitive skills and memory get worse, their behaviour changes and they need wide-ranging help in their everyday activities. At this stage, the patients need full-time assistance with day by day personal care, they forget recent experiences, have communication difficulties, and become prone to pneumonia and other infections. With the view to the pathology of AD, Bredesen (2009) posits that the disease is a neurodegenerative disease whereby neurons in different nuclei are lost during a specific distributions related to the disease. Still, the loss neutrons is a somewhat a late episode that normally follows the neurite retraction, synaptic loss, synaptic dysfunction, as well as the manifestation of other abnormalities. In this progression, the role played by the cell death programs is a secondary one during the process of neurodegeneration. According to Bredesen (2009), even though the cell death happens late during the neurodegenerative process, the pathways engrossed in the signalling of cell death play a crucial part in neurodegeneration, in both the sub-apoptotic events and the eventual neuronal loss. Cell death as mentioned by Behl (2000) could be divided into apoptosis as well as necrosis based on a certain morphological and biochemical features. The former is commonly recognised as programmed cell death (PCD), and it suggests that the interruption of the death program can halt neurodegeneration. Behl (2000) further mentions that different overlaps between apoptotic as well as necrotic cell death could happen and in due course the cell where the apoptotic pathway was initiated, ultimately leading to disintegration of the necrotic features. Therefore, apoptosis in AD could result in neurodegeneration in AD as well as its eventual pathology. The process of neurodegeneration could be caused by different types of insults such as reactive oxygen species and misfolded proteins and still generate a moderately reduced number of syndromes. Bredesen (2009) suggests that halting the neurodegenerative process completely could need therapeutics which addresses every interacting pathway. The brains of individuals with AD have neurofibrillary as well as , which are abnormal structures created by misfolded proteins. Neurofibrillary and amyloid plaques formations are believed to contribute to the neurons degradation within the brain and AD symptoms. Amyloid plaques accumulation between the brain’s neurons is considered to be one of AD hallmarks.  Generally, amyloid connotes the protein fragments normally produced by the body. In AD, Sadigh-Eteghad et al. (2015) posit that the beta amyloid (Aβ) accumulate to form plaques that are insoluble and hard. The Aβ influence the memory, personality, and social skills and eventually reduce the life expectancy and quality of life (Sadigh-Eteghad et al., 2015). The patient ability to function effectively in his/her day-to-day life could be influenced. The neurofibrillary tangles, on the other hand, are considered to be twisted insoluble fibres located in the brain's cells. Such tangles include a protein commonly referred to as tau, which creates the part of the microtubule. Basically, the microtubule plays a crucial role in the transportation of important substances such as nutrients in different parts of the neuron. The abnormality of tau protein leads to the collapse of the microtubule structures (Peng, 2008). The microtubules are important since they are transport system of brain neurons and they serve as safely guide as well as railroad tracks and transport information, molecules, and nutrients to other cells. In AD, the tau proteins’ chemical make-up is changed; thus, the tau threads become tangled as well as twisted. For that reason, the microtubules become disintegrate and unstable resulting in the collapse of the whole neuron transport system (Peng, 2008). Such events could be associated with the first noticeable symptom of AD, the memory loss. According to Guillozet et al. (2003), the medial temporal lobe regions have numerous neurofibrillary tangles, which is related to memory function and it is associated with the non-demented individuals’ memory tests performance. Guillozet et al. (2003) observed that in AD, the tangles have a pathological substrate that is associated with memory loss. With the view to the genetics of AD, researchers as cited by Bekris et al. (2010) have established that genetics play a crucial role in determining whether a person develops AD. Amongst the elderly, apolipoprotein E (APOE) is the gene most related to the early symptoms of the disease. A number of individuals having one or even two APOE e4 alleles are less likely to develop AD. The majority of people developing the disease do not have any APOE e4 alleles. However, a person with ‘AD gene’ is at high risk. For instance, CD33 gene increases the risk of developing the disease since it reduces the rate at which the body is eliminating the amyloid plaques. This results in the build-up of amyloid plaques which results in brain neurons degradation. The Early-Onset AD normally happens in people aged between 30 and 60 years, and accounts for no more than 5% of the individual with AD. The majority of the cases are attributed to the inherited change in any of the three genes, leading to as early-onset familial AD. Therefore, a child who either of his parents is a carrier of early-onset familial AD, there is 50% probability that he/she would inherit that mutation (NIA, 2016). In case he/she inherits the mutation, the child is more likely to develop the early-onset familial AD. According to NIA (2016), one of mutations on chromosomes 1, 14, and 21 result in the early-onset familial AD. All such mutations lead to formation of abnormal proteins. Therefore, chromosome 1, 14 as well as 21 mutations results in abnormal presenilin 2, abnormal presenilin and abnormal amyloid precursor protein (APP), in that order. All these mutations have a part in the APP cleavage. Basically, this breakdown is considered to be a process which results in dangerous types of beta-amyloid that result in amyloid plaques, the hallmark of Alzheimer’s. The APOE gene alleles (ε2, ε3, as well as ε4) are normally found in the chromosome 19. The APOE ε3 allele is present in 70% to 80% of the population and its role in AD is considered to be neutral. Between 10% and 15% of the population have APOE ε4 allele and it increases AD risk (Bekris et al., 2010). APOE-ε4 is considered to be a high APOE gene risk variant, and is mostly related to increased late-onset AD risk. On the other hand, homeostatic scaling, which is a type of synaptic plasticity is regulated by the presenilin 1 (PS-1) gene. The homeostatic scaling is defined as a mechanism for protecting the brain cells to make sure that the neurons do not drastically change their firing patterns while responding to environmental changes. More importantly, homeostatic scaling deficits could result in AD development amongst people giving the PS-1 mutations. There are different steps in AD progression present possible treatment targets; for instance, Lansdall (2012) established that the accumulation of insoluble plaque formation and pathogenic Aβ peptide species could trigger numerous harmful processes, such as tau hyperphosphorylation that result in neuronal death. As mentioned by Wlassoff (2014), tau hypothesis and amyloid hypothesis are major theories that scientists formulated while trying to explain the AD development. As evidenced by their name, the corresponding proteins are considered by the hypothesis as key players in AD development. Basically, the Tau hypothesis is attributed to the fact that tau tangle pathology happens before the formation of Aβ plaque formation and is associated closely with progression as well as severity as compared to Aβ plaque load. Understanding that the mechanism through which tau and Aβ and interact provide possible treatment targets for the disease. The tau hypothesis blames the neurofibrillary tangles formation for the AD progression. As mentioned by Lansdall (2012), Aβ pathology in the years before dementia’s clinical onset allows for the continued clinical trials to examine the Aβ-targeting therapeutics within the prodromal AD. These ongoing trials offer a definitive solution with regard to the value of treatment approaches that targets the Amyloid Hypothesis. According to the amyloid hypothesis, the Aβ is the main cause of AD. Even though the tau- and amyloid-targeting therapeutics could still prove independently successful, Lansdall (2012) is of the view that the highly AD pathology complex nature provide evidence that the intervention that would prove effective would not involve a one-drug wonder; instead, a combined therapy would without doubt comprise an ultimate step in developing a cure. Section 2 At present, AD has no exact treatment or cure, but its symptom can be alleviated. The current treatments do not have the ability to stop the progression of Alzheimer's, but they can momentarily slow the symptoms from worsening and also enhance the patient’s quality of life. There is a global effort intended for finding the best way to treat AD, delay its onset, and stop its progression. Given that it takes many years before AD symptoms start appearing, therapies could not be tested early during the disease process. However, advancement in biomarkers and imaging has allowed the researchers to easily detect the earliest symptoms of brain changes associated with the disease. Furthermore, many volunteers have been recruited by clinical trials with the objective of finding a cure for the disease. The majority of trials are searching for ways to delay or prevent the onset of the disease; therefore, they are recruiting volunteers who are cognitively healthy but also at risk of developing the disease. For instance, the NIA-funded clinicians and researchers as cited by NIA (2012) have been testing interventions with the objective of lessening psychiatric symptoms and conditions related to AD, which includes depression, agitation, and apathy. Such symptoms and conditions result in more distress for people with the disease together with the caregivers, since it becomes challenging to offer care and result in cognitive decline cognitive skills. The NIA is currently supporting numerous clinical trials with the objective of finding treatments that could delay the start of the symptoms as well as the progression of the disease. The existing AD treatments improve the problems with reasoning and thinking as well as signs of memory loss for a temporary basis. These treatments improve the chemicals’ performance in the brain, where information is conveyed between the neurons. Still, the treatments cannot stop the underlying brain cells’ decline as well as death. AD progresses when more brain cells die. The drugs/treatments that are currently available include cholinesterase inhibitors and memantine. Taking Cholinesterase inhibitors is considered to be beneficial to people with AD since they help treat a number of symptoms such as improving communication, memory, thinking, or daily activities. In essence, the cholinesterase inhibitors affect the neuron communication’s chemical by making sure it continues to work for longer. As a result, the manner in which the brain send signals is improved; thus, reducing the symptoms of the disease for some time. Given that cholinesterase inhibitors do not stop the disease progression, AD symptoms could worsen after some time. Still, it helps a number of patients to function a little higher as compared when they are not using the drug. Some of the cholinesterase inhibitors normally used to treat the disease includes donepezil, galantamine, and rivastigmine. Even though Alzheimer's has no cure, two drugs (rivastigmine as well as donepezil) are currently utilised to help reduce Alzheimer's disease symptoms. The objective of both drugs is to restrain acetylcholinesterase, which is an enzyme that inactivates acetylcholine (ACh) at the synapse. Basically, restraining this enzyme stops the ACh breakdown and is considered as a means of compensating the lowered ACh concentrations that typify Alzheimer's disease. Memantine is considered as a suitable option for a person with severe AD and also for those with moderate AD in case the cholinesterase inhibitors are deemed unsuitable. Normally, memantine is supplied as a liquid or tablet and helps with numerous symptoms. This type of drug is only recommended for AD patients and facilitates the communication between the neurons in the brain. The drug enables the neurons to receive messages which consequently improve the signals transmission in the brain leading to the reduction of AD symptoms. The disease symptoms can also be alleviated using non-drug treatments such as cognitive therapy, regular exercise, and improved nutrition. Memantine according to Alzheimer Society of Canada (2011) is a N-methyl-D-aspartate (NMDA) receptor antagonist, whereby the glutamate molecules targets that the neurons release are received by the NMDA receptors. The interaction of NMDA receptors and glutamate molecules make them serve as ’neurotransmitters’, whereby message is passed from one neuron to another. Therefore, memantine normally prevent the interaction of NMDA receptors with glutamate molecules; thus, reducing the excess glutamate toxicity. This leads to the normalisation of the nerve messages transmission between neurons. The drugs used to treat AD have some side effects as shown in the table below sourced from NIA (2016); Name of the Drug Type and use of the drug How it functions The side effects Aricept (donepezil) It is a cholinesterase inhibitor used to treat various symptoms associated with AD regardless of the stage. Helps stop the acetylcholine breakdown in the brain. Fatigue, loss of weight, diarrhoea, vomiting, nausea, as well as muscle cramps. Exelon (rivastigmine) It is also another type of cholinesterase inhibitor mainly used to treat symptoms of AD (mild and moderate) Helps prevent the butyrylcholine and acetylcholine breakdown in the brain Indigestion, vomiting, diarrhoea, nausea, muscle weakness, and loss of weight. Namenda (memantine) It is a type of Memantine used mainly to treat moderate as well as severe Alzheimer's Obstructs the toxic effects related to surplus glutamate and controls activation of glutamate. Constipation, diarrhoea, dizziness, confusion, and headache. Namzaric It is a cholinesterase inhibitor and N-Methyl-D-aspartate antagonist utilised in treating symptoms of severe and moderate AD (for people that have been stabilised on both donepezil as well as memantine taken separately) It obstructs the toxic effects related to surplus glutamate and also stops the acetylcholine breakdown in the brain. Diarrhoea, headache, dizziness, and nausea, and vomiting. Razadyne (galantamine) It is a type of cholinesterase inhibitor used for treating symptoms of moderate and mild AD. Stops the acetylcholine breakdown and ensure more acetylcholine is released in the brain by stimulating nicotinic receptors. Reduced appetite, vomiting, diarrhoea, and dizziness. With the view to Winblad et al. (2016) study, they identified some epidemiological studies which identified the possible protective and modifiable risk factors which could be targeted in AD prevention programmes. In this regard, randomised controlled trials (RCTs) are used to ascertain whether prevention strategies targeting protective and potential risk factors as well as could substantially reduce AD incidence. In the last 10 to 15 years, numerous clinical trials and observational studies have identified different protective and modifiable risk factors that augment AD risk (Winblad et al., 2016). For instance, the midlife’s vascular risk factors like diabetes, cholesterol, high blood pressure, and obesity have been associated with AD later in life. Other possible risk factors include psychosocial factors, like stress, loneliness. The NIA (2012) have carried out numerous clinical trials such as A4 Trial, whereby an amyloid-clearing drug was tested on 1,000 older volunteers that were free from AD symptoms but with abnormal amyloid levels which had been detected through brain scans, especially the positron emission tomography (PET). Other clinical tests that have provided promising results include the API APOE4 Trial, Dominantly Inherited Alzheimer Network (DIAN) Trial, as well as Alzheimer’s Prevention Initiative (API). Currently, there are some promising interventions that are being developed such as Solanezumab, which is drug in research that seeks to reduce the beta-amyloid level in the brain to prevent the formation of plaques. Verubecestat is another drug in research that seeks to inhibit the beta-secretase enzyme ability to form beta-amyloid. AADvac1 is a vaccine in research that would be used to stimulate the immune system of the body to attack all abnormal forms of tau protein which destabilise the structure of the neurons. The last drug in research is the Intepirdine, which seeks to block the ability of the receptor to reduce the levels of acetylcholine (Alzheimer's Association, 2017). Section 3 Currently, the best standard of care is cholinesterase inhibitors since they offer a first-line and standard treatment for AD. According to Yiannopoulou and Papageorgiou (2013), the systemic reviews together with numerous RCTs have provided evidence indicating that cholinesterase inhibitors are beneficial to cognitive activities and functions of people with the disease, especially the mild to moderate AD. As pointed out by Barnett et al. (2014), early diagnosis has an effect on the treatment outcomes; for instance, it is cost effective. Thanks to technology advancement, it has become easier to detect AD earlier enough to facilitate earlier intervention. There are numerous tools and methods used by medical practitioners to determine whether their patients have an AD. The disease can be diagnosed through inquiry, whereby the doctor talks to the person or a member of his/her family regarding the past medical problems, overall health, the person’s ability to perform day-to-day activities, as well as personality and behaviour changes. Besides that, AD can be diagnosed through tests of language and memory. Besides that, medical tests like urine as well as blood tests can also be used for diagnosing the disease. Nowadays, brains scan such as computed tomography (CT), positron emission tomography (PET), and the magnetic resonance imaging (MRI are currently used to identify signs of AD (Alzheimer's Association, 2017). The magnetic resonance imaging (MRI) is normally utilised by doctors to rule out some of the conditions that result in cognitive symptoms. Furthermore, doctors utilise MRI scans to determine whether the brain regions’ shrinkage has happened since it is normally associated with AD (Alzheimer's Association, 2017). On the other hand, computerized tomography (CT) is used to produce brain cross-sectional images which are used to rule out head injuries, strokes and tumours. The PET scans are used to show the brain parts that are not functioning effectively. More importantly, the new PET techniques enable the doctors to detect the level of tangles (tau) as well as plaques (amyloid) in the brain, considering that they are two abnormalities associated with Alzheimer's. Cognitive tests are normally utilised to evaluate and measure the thinking or cognitive functions like language skills, concentration, memory, as well as visual-spatial awareness. Basically, cognitive tests are considered to be vital in diagnosing AD and dementia. Normally, doctors use these tests to examine the patient‘s mood and could help in diagnosing depression that could result in symptoms that are same as those of AD. Some of the common cognitive tests used include: Mini-Mental Status Examination commonly used to diagnose dementia and normally involves examination of various skills like writing and reading. Another type of cognitive tests includes, Alzheimer disease Assessment Scale-Cognitive (ADAS-Cog) which is normally used for people having mild symptoms whereby their language and memory skills are examined (Skinner et al., 2012). With the view to pathological diagnosis, neurofibrillary tangles cannot be seen easily while using the eosin, hematoxylin and morphological stain. According to Perl (2010), some of the silver impregnation staining methods, like the fluorochrome dye thioflavin S or modified Gallyas technique can be used to visualise the neurofibrillary tangles. Besides that, numerous immunohistochemical techniques could also be utilised to visualize tangles. Using the special stains, it is easy to identify the tangles which normally appear as thickened, parallel fibrils surrounding the nucleus as well as extending in the direction of apical dendrite. In AD, the neurofibrillary tangles distribution pattern is somehow predictable as well as stereotyped. With regard to Plaques, immunohistochemical techniques can be used for diagnosis whereby antibodies are raised in opposition to the βA4 molecule portions (Perl, 2010). The diagnosis of AD can be achieved definitely after death, whereby brain tissue examination and clinical measures are linked together during the autopsy. Blood tests allow the doctor to exclude other possible causes of confusion and memory loss, like vitamin deficiencies or thyroid disorders. Neuropsychological and mental status testing enable the doctor to examine the patient’s mental functionality, memory as well as other thinking skills. Brain imaging has become a crucial tool for diagnosing AD since it helps the doctors to see abnormalities associated with other conditions like tumours, trauma or strokes that could bring about cognitive change. The new imaging applications allow the doctors to detect certain changes in the brain attributed to the disease. The current research into diagnostic tools focuses on incorporating technological advances and insights to improve diagnosis, make AD brain changes autopsy stronger, and create a research agenda for improving diagnostic accuracy. Conclusion In conclusion, it has been observed that AD’s first symptoms often vary from one person to another; still, the first cognitive impairment sign associated with this disease is memory problems. The disease can result in financial challenges since the costs related to taking care of a person with AD are exceedingly high. Some of the costs are associated with pharmaceuticals, diagnostic tests and physician care. According to epidemiological studies, the risks associated with AD can be reduced through mental activity, physical exercise, as well as dietary measures. Incidents of dementia can be protected by Statins while the same benefits can be conveyed by lithium to the bipolar patients. Currently, there are number of promising drugs being developed and tested, but to make sure that fresh ideas are generated, federal research funding and complete clinical trials have to be increased. New guidelines for AD diagnosis have been developed based mainly on the brain structure. This would facilitate early detection, but there is need for validation studies that would help improve the accuracy as well as sensitivity of such new measures. Blood tests facilitate the exclusion of other possible causes of confusion and memory loss. As mentioned in this paper, early detection is beneficial because it enables people to easily get treatments as well as take part in clinical trials and support services. More importantly, people with the disease together with their caregivers would be able to develop health directives in advance and also make legal as well as financial arrangements prior to the further declination of the cognition. Furthermore, they would be able to manage the safety issues and look for counselling regarding the ways of coping with behavioural changes related to the disease progression. When AD is detected early, the health caregivers would be able to deliver the best care to the patient. References Alzheimer Society of Canada, 2011. Memantine hydrochloride. [Online] Available at: HYPERLINK "http://www.alzheimer.ca/~/media/Files/national/Drugs/Drug_Memantine_e.pdf" http://www.alzheimer.ca/~/media/Files/national/Drugs/Drug_Memantine_e.pdf [Accessed 31 January 2017]. Alzheimer's Association, 2017. 2016 Alzheimer's Disease Facts and Figures. [Online] Available at: HYPERLINK "http://www.alz.org/facts/" http://www.alz.org/facts/ [Accessed 23 January 2017]. 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