The Effects of Ageing on Alzheimer's Disease - Research Paper Example

Effect of Ageing on Alzheimer’s Diseases s The life span of all organisms that exist includes the ageing period. Ageing maybe defined as functional and structural deterioration of physiological functions of the body. With increases in age cells of the body gradually lose their normal functions till they reach a stage when they fail to function adequately at all. Therefore cellular senescence i.e. the sudden inhibition of growth in mitotic cells causes impairment of functioning. Cells that are senescent are primarily responsible for ageing and age-related disorders owing to a feature of such cells-Senescence associated secretory phenotype. Cell proliferation is inhibited by cellular senescence which maybe triggered by various factors. There is not enough evidence to pinpoint just a single cause for ageing and so far it is assumed that the process of ageing is initiated by different factors. The most widely known factor is that of oxidative damage. According to the oxidative damage theory, the body’s own metabolism is the most important contributor of the ageing process. The mitochondria takes up oxygen and 2-3% of the oxygen it takes up is reduced to reactive oxygen species such as superoxide, hydroxyl and hydrogen peroxide ions. These reactive oxygen species damage cell membrane structure, nucleic acids and proteins. Another important theory is that of damage to the mitochondrial genome in a an individual. It has been seen that the mitochondrial genome mutates at a much faster rate than the nuclear DNA and these erratic mutations have been linked to apoptosis or production of Reactive oxygen species. With age mutations in mitochondrial cells increases and leads to several problems because fo the higher replication frequency of the mutants (Michikawa et al,1999). Wear and tear theory is the oldest one used to account for loss of normal functioning of cells. With increases in age the body’s small problem tend to build up. Wear and tear associated with genetic instability has been studies in-depth. Mutations would increases in number without any repair and enzymes produced would be faulty as well. When our cells become faulty they are repaired by the DNA repair mechanism and therefore it is obvious that a cell whose DNA repair enzymes are in working condition lives longer (Hart & Setlow, 1974). However, the most important and relevant factor to the process of ageing are genetic processes. The most important example of this is Progeria, where genetic mutations rapidly enhance the rate of ageing in an individual. Mutant gene studies and study of long living organisms has provided researchers with valuable insights into the process of ageing. SIR2 is one such gene whose expression is known to increase lifespan by acting on biological processes (Hekimi & Guarente,2003). Almost 25 million people around the world have been diagnosed with dementia and most of these cases are that of Alzheimer’s alone (Qui et al,2009). It has been projected by the US centre for Diseases control and Prevention and the UN Aging program that the number of older people afflicted by Alzheimer’s would be nearly 1 billion by 2030(CDCP,2008 & UNO, 2001). This is more likely since the in the coming years the proportion of the elderly in every population would rapidly increase and since age is perhaps the most important factor for Alzheimer’s an aging population automatically becomes a susceptible one. Below is figure 1- demonstrates that the percentage of the geriatric population of both the genders would be increasing in the coming years and since Alzheimer’s is related to ageing there is a high chance that a high number would also be diagnosed with Alzheimer’s. We can see that in 1950 the geriatric population was actually less for both genders. However, when we compare this to projections to 2030 we can clearly see that population of the elderly have risen. The number of people being diagnosed with dementia and related conditions is always on the rise and Alzheimer’s is the most common form of dementia. In the U.K. alone almost 800,000 people were diagnosed with some form of dementia. Only 17,000 people of the above were under 65 years showing that with increase in age prevalence of the disease also increases. 1 in every 25 people between the age group of 70-79 years suffers from dementia especially Alzheimer’s (Alzheimer’s Society,2012) . In the Figure below it is clear that between the age group of 70-79 years,6.67% of the female population and 5% of the male population develop dementia. Age-related diseases Ageing itself is not the sole problem today because with the problem of ageing comes the risk of age-related diseases which today are among the most common causes of death. Several researchers have tried to derive links between cell senesce and complex diseases. These age related diseases have pathologies at the molecular and genetic level. Diseases such as diabetes, cancer and dementia are well known age-related problems owing to the reduced resistance capability and repair ability of the body systems. Today, dementia is one of the most important diseases that pose a threat to human well being and Alzheimer’s is one of the major forms of dementia. Alzheimer’s is a neurodegerativedisease which exists mostly among the ageing population. Alzheimer patients become dependent on someone else even for completion of routine tasks. The major effect of the disorder is seen in the impairment of cognition since the patient loses his memory, speech, ability to think or understand and other brain functions as well. It has been seen that with increase in age the susceptibility of a person increases and the risks also increase leading to development of the problem, hence we may say age is the main risk factor in Alzheimer’s. Research studies have established links between cell senesce and AD. Cells such as microglia which is present in the CNS and responsible for normal functioning of neurons tend to lose their functioning with age leading to dystrophy of the cells and impairment of the neuronal functioning which ultimately leads to neuronal cell death followed by Ad (Flanary,2005). In this report I have tried to establish the relation between ageing and Alzheimer’s and how ageing actually increases the chances of diseases development. The following are the main objectives : Examining the role of genetics and other relevant factors Pathophysiology of Alzheimer’s Scans Tretaments The etiology of Alzheimer’s is highly complex. The disease is caused by a combination of genetic, lifestyle and environmental factors which interact between themselves to alleviate the chances of diseases development. Age is considered one of the most important parameters in this case since with increase in the body’s defense and repair mechanism deteriorates. Owing to ageing, an individual becomes more susceptible to risk factors such as head injuries, diabetes and other health factors. Genetics plays an important role in disease onset. Mutation tend to cluster within a family thereby increasing the risk of inheritance and causes familial Alzheimer’s. Genetic mutations on chromosome 21, 14 and 1 cause familial Alzheimer’s (Cumming et al, 1998). With advancement in age, a person becomes more susceptible to such mutational changes and hence old-age enhances chances of disease onset. Figure below shows the prevalence of familial AD owing to mutations in gene 21,14 and 1. However besides the mutation risk of familial genes, inheritance of the apo4e gene increases the risk of onset of the diseases. Inheriting two copies of the gene increases chances of diseases development by 10 times. However all this depends on age and the human brain has to reach a certain age to become susceptible to the impacts of these genes; therefore age plays an important role in diseases development. Diet also plays an important role and is a major risk factor. Dietary fat and total calorie intake were recognized as major contributors. An acid-forming diet “as one high in dietary fat or total energy, can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress potentially leading to the neurological damage characteristic of AD” (Grant et al,2002). Grant et al used mice models to study the association. They fed these models with diet high in dietary fat while the control set was given normal food. The neurological damage was studied in both of these sets and post sacrifice the brain tissues were studied to compare the extent of damage. Some studies have also focused upon the role of elevated metal concentration in the brain leading to Alzheimer’s’. Metals such as Aluminum, copper, iron and zinc are thought to be associated with the development and progress of the disorder (Scherbatykh & Carpenter, 2007).Bertram et al(2007) performed systematic analysis of 127 polymorphisms on about 69 genes that are associated with AD.Using further statistical analysis Bertram et al have pinpointed a number of genes (ACE,CHRNB2, ESR1 etc) responsible for AD and have calculated the significant risk of the alleles as between 1.11-1.38 which is quite high. Nicoll et al (2013) studied tissue and DNA samples of 233 dementia patients and performed both genetic and statistical analysis and found that Interleukin-1A2, 2 genotype was seen in almost 13% of the subjects. The study however fails to prove the significant association between the presence of the allele and onset of Alzheimer’s Pathophysiology Basic research has been conducted to understand the underlying issues associated with Alzheimer’s. Several studies have established that the pathophysiology of the disorder associated “with a variety of factors, including the extracellular deposition of b-amyloid (Ab) plaques, accumulation of intracellular neurofibrillary tangles, oxidative neuronal damage, and inflammatory cascades” (Imbimbo, 2005). However the most important factor that is believed to be a significant contributor towards the pathogenesis of the diseases is the enhanced production of Aβ peptide which is in fact the main component of the extracellular amyloid plaques that are considered the hallmarks of the diseases.Mutation in the APP gene is one of the major causes of the disorder. APP gene mutation was first discovered in familial study (Goate et al,1991). Goate et al, studied the families with both late and early onset of familial Alzheimer’s and found that recombination took place between the APP and AD gene loucs.The genetic mutation in the APP gene leads to altered production of Aβ . Accumulation of this leads to formation of plaques which degenerates neurons leading to neuronal loss and aiding impairment of cognition. Mutations on other genes have also been seen to occur. These genes includes presenilin 1 which is present on chromosome 14 and presenilin2 which is found in chromosome 1 (Levy-Lehad et al,1991; Sherrington et al,1995). Sherrington et al, conducted genetic linkage studies on subjects with AD and isolated 19 transcripts encoded within the region around the chromosome locus 14q24.3. They found missense mutations associated familial AD whereas patients kept as control did not show such mutations. In fact the process of ageing facilitates the onset of the diseases. Mice models have shown that increase in age more senile Aβ plaques are formed (Finch,1994).For this Finch used mice in the laboratory settings and observed them throughout their life span and detected development of plaques causing abnormal behavior especially among the older mice population. Another equally important neuropathologic hallmark of Alzheimer’s is the neurofibriallary tangles. The tangles are formed owing to hyperphosphorylation of tau protein paired with helical filament. These lesions are formed in the early stages of the disorder and gradually lead to loss of cognitive ability as well as memory. The tau protein is present within the neurons. The most important function of the tau protein is to bind microtubules thereby supporting axonal transport. In fact, the integrity of the axon entirely depends on the binding of the tau protein to microtubules. There exists six different isoforms of the tau protein in the human brain. The different isoforms of the protein is phosphorylated which determines the binding capability of the tau protein to microtubules.Hyperphosphorylation of the tau protein takes place in Alzheimer’s.Ithas been seen that Hyperphosphorylation increases with age and therefore there is increased chances of development of the tangles leading to onset of AD. Once the protein is hyperphosphorylated, it detaches itself from the microtubules and the misfolded tau protein aggregates. This in turn destabilizes the microtubules to which the protein had attached and also disrupts with axonal transport which ultimately leads to death of the neural cells.However, the molecular mechanism that causes these Hyperphosphorylation is not well understood at the moment. However there exists substantial evidence that the problem in regulation of tau protein enzymes like kinase and phosphatase are responsible. Tau protein is phosphorylated by kinase and de-phosphorylated by phosphatase thereby maintaining a balance. However, imbalance in this regulation leads to Hyperphosphorylation. This imbalance increases with age and in the ageing population the expression of kinases increases owing to which the rate of phosphorylation far exceeds dephosphorylation thereby causing a problem (Feldman,2007). The cholinergic hypothesis is one of the major focus of AD research. It is well known that the cholinergic pathways of the forebrain (basal and rostral) play an important role in maintaining the cognitive ability, memory, attention and pneumonic processes in humans. However, it has been seen that AD patients have profound damage in these pathways. Therefore loss of cholinergic functioning in the brain aids cognitive declination and is suspected to be a major reasons for Alzheimer’s onset.(fig 5.1).(Terry & Buccafusco,2003). The researchers basically based their finding upon assays of post mortem enzyme activity. Terry and Buccafusco studied both humans and AD patients (both post mortem and antepost mortem) and saw that abnormal cholinergic activity was associated with AD. The experiment was supported by similar experiments done by Terry and Buccafusco on animal models as well and therefore is a very important evidence for the hypothesis. Symptoms Alzheimer’s disease has been described in DSM-IV as a type of dementia in which memory deficiency is quite noticeable. At least one cognitive deficiency like theof problem-solving ability, judgment, recognition, speech and impairment of other learned motor skills is prominent. The diseases symptoms may be primarily divided into three different stages-Early stage, middle stage and later stage (NHS, 2014). Early stage- Most symptoms are mild and often confused with natural ageing symptoms. This includes forgetfulness, poor judgment, confusion and mood swings. Middle Stage-In this stage the memory worsens. The patient forgets most of the things, suffers from confusion, hallucinations and delusion, loss of spatial cognition, speech problems and mild insomnia. Later symptoms- At this stage the patient requires full-time care and becomes fully dependent on his/her care takers. All the symptoms becomes severe with loss of both short and long time memory, enhanced delusions and disorientation. Owing to delusions behavioral changes also emerge and the patient becomes violent and sometime depressive. Physiological manifestations tend to surface at this stage with urine inconsistency or bowel inconsistency, difficulty in swallowing and sudden weight gain or loss. Diagnosis The most important thing to understand about the diagnosis of Alzheimer’s is that there is not just one single test which can help determine the onset or the progress of this disease. Ageing also does not help this since most of the symptoms of Alzheimer’s are easily confused with that of ageing. A thorough medical evaluation is needed in order to diagnose the disorder. Research based on the diseases has come up with a few diagnostic tests which may be utilized for detection of the disorder. Gasparini et al (1998) suggest the use of peripheral markers for detection of the diseases. The use of peripheral tissues especially skin fibroblasts would help in assessment of signal transduction pathways and processing of amyloid precursor protein. The 5 word diagnostic test is a relatively simple and non-invasive tool for diagnosing the disorder. The test primarily requires the patient to recall short list of 5 words only after thorough registration in the brain. Research on this diagnostic tool reveals that the specificity of this is 87% thereby making the test a rapid and relatively easy diagnostic tool for detection of memory disorders especially Alzheimer’s (Dubois et al,2002). 7.1:Diagnosis based on New research Newer research has come up with a few more diagnostic tool that would assist in diagnosing the disorder quite early to help initiate management program for better management of the diseases. Rye et al (2011) conducted an gene expression analysis on the RNA from blood samples collected from suspected Alzheimer’s patients The test results revealed a clinical accuracy of 80% making gene expression test of blood samples an important diagnostic tool for detection of the disorder on during its early stages however the tool needs further research to help confirm the findings of the reliability of this tool.. Scans Earlier the sole methods of assessment of the disorder basically focused on psychological, cognitive and memory testing however today, the neurodegenerative disorder may also be assessed by scans and neuroimaging of the brain. 8.1 Structural Imaging Research studies have established that structural neuroimaging is a rapid, cheap and reliable technique for determination of the onset of the disorder. The studies reveal that MRI images which gives a measure for early entry and conversion to Alzheimer’s has significant clinical importance.The images where the “ initial degree of Hcp atrophy, and also the combination of areduced temporal neocortex and an atrophied Hcp or anteriorcingulate cortex, may be the most significant predictorsof progression to AD” (Chetelat& Baron,2003). 8.2 Functional Imaging Functional Imaging in Alzheimer’s consists of SPECT scan or PET scan. These scans utilize glusoce or oxygen and gives images of hyperperfusion in the biparietal, bitemporal and bilateral regions of the brain. Changes in these areas of the brain occur quite early in the stages of the disease and therefore are important in understanding the neurochemicals systems as well (o’Brien,2014). 9.0: Treatments Alzheimer’s is a complex disorder and therefore the treatments that exist today are unable to cure the disorder because of the multi-faceted nature of the problem. Most of the treatment options that are available today primarily focus on delaying or preventing degradation of cognitive ability, mental functioning and other symptoms associated with the diseases. Pharmacological treatments of the diseases depends on just four marketed drug options all of which are cholinesterase inhibitors- tacrine, donepezil, rivastigmine and galantamine (Allian et al, 2003). Newest Research On Alzheimer’s Treatment options The aim of the present research studies that are being conducted is to develop cost effective, rapid and reliable treatment options for management of the diseases. Arendash et al (2011), established that long term exposure to high frequency electromagnetic field(EMF) has beneficial effects on the cognition of a person. The tests were conducted on both normal and transgenic mice that were exposed to EMF.It was seen that in mice suffering from Alzheimer’s the exposure to the high frequency radiation helped decrease the amyloid beta plaques. The study therefore suggests that EMF maybea non-invasive method of treating the problem. However, the need is to orient the research of the effects of EMF on humans. Reliable pharmacological options are also being researched upon. The four primary drugs that are available focus on controlling the symptoms of the disease but have no control on its progression. Some disease modifying drugs have been developed so far.Most of “these reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches” (Salomone et al,2012). However none of these drugs s of yet has passed the phase 3 of clinical trials which shows that more research is also needed on understanding the pathophysiology and biology of the diseases as a whole. Conclusion Alzheimer’s is today one of the major problems especially among the ageing population. It poses a considerable challenge towards the geriatric management policies. The sole way to accurately diagnose and manage the disorder is to orient the research upon understanding the biology and pathophysiology of the problem. Future research should try and obtain an indepth understanding of the pathophysiology of the disorder in order to help design corresponding pharmacological treatments. Another major area for future research should focus on diagnostic tools. Early diagnosis helps in better management of the diseases and therefore more research must aim towards finding out better diagnostic tools which would not only be rapid and accurate but also be cost effective as well enabling one to diagnose the problem in its early stages. Biomarkers need to be understood as well since they make early detection much simpler. Even though at present we do not have much biomarker to help in clinical detection, the focus of research should be towards development of reliable biomarkers for the disorder. Thus, the most important method of tackling this neurodegenerative problem is to enhance the research strategies and increase our understanding of the same. REFERENCES Alain, H., Bentué-Ferrer,D., Tribut,O., Gauthier.S,, Michel.B.F. & Drieu-La Rochelle.C., (2003), “ Alzheimers disease: the pharmacological pathway”,FundamClinPharmacol, 17(4), 419-28. 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