Alzheimers disease is a condition that comprises of dementia which leads to life threatening condition. Patients are increasing at a faster rate. Diagnosis is done on basis of mini mental status examination and physical examination of the patients. Acetyl cholinesterase inhibitors and N-methyl D-aspartate Inhibitor (memantine) are available as current treatments. These medications have gastrointestinal side effects and these are not able to control disease progression. Novel therapies are available with different approach but their efficacy is objectionable as less patients participate in trial and some patients do not complete the trial and ethical issues. Alzheimer's researches need support to get rid of this disease. Novel therapies can give promising results.
Dementia comprises of progressive memory impairment along with either aphasia that is inability to generate coherent speech or apraxia that is inability to execute motor activities or agnosia that is difficulty in identification of objects, person or sound. There are several forms of dementia like vascular dementia in which lack of oxygen supply to brain leads to vascular lesions. It is another most common cause of dementia after Alzheimer's disease. Dementia with lewy bodies is the one in which abnormal aggregate of proteins; clumps of alpha-synuclein are present inside nerve cells.
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Alzheimer's disease is the most common form of memory problem(dementia). It can be classified into seven stages. Early onset Alzheimer's disease which refers to the cases diagnosed before the age of 65 years. Late onset Alzheimer's disease which refers to the cases diagnosed after the age of 65 years and familial Alzheimer's disease which is transferred from one generation to other. Early onset Alzheimer's cases account to be less than 10% of total diagnosed cases so more than 90% of total Alzheimer's patients are of late onset .On basis of disease progression it can be classified into different stages. Stage 1 is characterised by no impairment in memory, judgement or any daily activity. In stage 2 patients might experience lapses in memory but these changes cannot be detected. In stage 3 changes in memory becomes noticeable. Alteration in communication pattern or behaviour can be detected. In stage 4 declines in cognitive ability becomes more prominent and it can be detected by most people. In stage 5 some assistance is required to patients related to daily tasks. In stage 6 patients face behavioural and personality changes so this condition is difficult to handle and caregivers found lots of difficulty to handle patients. Finally in stage seven patients loose contact with surroundings and there is no longer possibility that patient can respond to surrounding.
Worldwide burden of Alzheimer's disease
Worldwide record showed that 26.6 million people were living with Alzheimer's disease in 2006. Total estimated worldwide costs of dementia will increase by 1% of GDP and estimated to be $604 billion. About 70% of cost is from Western Europe and North America.
Report made in March 2010 by Alzheimer's association showed 5.3 million people in US as victim of this disease and it's the 7th leading cause of death so its the great matter of concern.
Alzheimer's research trust's "Dementia 2010" revels that more than 820,000 people in US are living with Alzheimer's and other dementias.
Dementia India report 2010 showed that India 37 million people are suffering from dementia and this is expected to get doubled in 2030. It reflects that this disease is progressing at a faster rate.
There are several factors that can be held responsible for generation of Alzheimer's disease. These factors include age, family history and genetics. All of these are not in our control. Age is the strongest risk factor for this disease as most of the people suffering from this disease are of age 65 years or above. The probability of developing Alzheimer's disease after 65 years gets doubles in five years. After age of 85 years likelihood to develop this disease is 50%.
Family history is another major risk factor which is commonly observed in most of the patients. Risk increases when more than one family member is suffering from this disease. Environmental factor or heredity can be the possible reason for this.
Genes are associated with Alzheimer's disease and are responsible for developing this disease. Mutation in gene is another risk factor to increase the chances for developing this disease.
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Several other factors are there like head injury, although probability for head injury to cause this disease is relatively less but a serious head injury can lead to increase in future risks to develop Alzheimer's disease. This factor is under our control. Diabetes is another risk factor which contributes to Alzheimer's however mechanism for this is not known.
Recently a study in 2010 showed a close relation between insulin deficiency and Alzheimer's disease. Alzheimer's disease transgenic mice model was used and mice were provided with Straptozotocin which is toxic to beta cells. To this mice respond by increasing the blood glucose level and decreasing the serum insulin level. Progression of beta amyloid precursor protein was seen. This provided strong evidence that diabetes is one of the risk factor for Alzheimer's disease. Further study on this can contribute to understanding the pathology of Alzheimer's disease and can lead to generation of ideal compound which can control disease progression. (Olin et al. , 2010 )
Pathology, diagnosis and Clinical symptoms
Cortical atrophy which involves medial temporal lobe of brain is macroscopic feature of Alzheimer's disease. Mutation in either presenilin gene or amyloid precursor protein leads to accumulation of beta amyloid which forms amyloid plaques resulting in neurofibrillary tangles and ultimately cell death. Exact cause of Alzheimer's disease is still not known. ( Science daily 2010)
Diagnosis includes knowing patient history, mini mental status examination and physical examination. Patient history is prepared on basis of series of questions asked by physician to the patients which include patient identifying information, difficulty in daily life, past medical history, medication being taken, psychosocial history as marital status, employment. Mini mental status examination is done to check the problem solving ability of the patients. Physical examination involves analysing body temperature, pulse rate and blood pressure. Symptoms of Alzheimer's disease can be broadly classified into two categories. Cognitive symptoms that affect memory, judgement, language, planning, ability to pay attention and other thought process. Psychiatric and behavioural symptoms which affect the way people feel or act. Common symptoms are memory loss, problem with language, disorientation to time and place, poor or decreased judgement, change in mood or behaviour, loss of initiation, inability to acquire new memories and difficulty in performing familiar task.
Available treatments and their limitations
Two categories of medications are prescribed as therapy for Alzheimer's disease. First category involves cholinesterase inhibitors which are galantamine, rivastigmine and donepezil. Tacrine was also used earlier but it causes hepatotoxicity so not in practice now. These medications indirectly provide cholinergic action by prolonging the life time of endogenously produced acetylcholine. Second category involve N-methyl D-aspartate antagonist which is memantine. It acts by blocking the current flowing through channels of NMDA receptors. Cholinesterases are prescribed in case of mild to moderate Alzheimer's disease while memantine is prescribed in moderate to severe Alzheimer's disease. Dose for donepezil starts from 5mg and target dose is 10mg daily. Rivastigmine starting dose is 1.5 mg twice daily. It is taken with food at two week interval. Target dose is 3mg twice daily. These are the only approved medication by FDA for treatment of Alzheimer's disease and it is because no other medications have more or even equal therapeutic effects than these medications.
Both type of medication provide symptomatic relief only and for limited period. Common side effects of memantine include headache, dizziness, constipation and confusion while for cholinesterase inhibitors side effects are nausea, vomiting, diarrhoea, weight loss and loss of appetite so both type of medication possess gastrointestinal side effects. Donepezil can cause complication during anaesthesia so it is advised not to take this drug if you have to take anaesthetic exposure and in cardiac patients it leads to bradycardia that is lowering of heart rate. Rivastigmine is supposed to be used with caution in case of asthma patients and patients with other lung diseases.
Average cost for these medications lies between $148 to $195 per month and not every patient give appropriate response. None of these medications is available as generic drug. Keeping all these things in consideration there is requirement for novel therapies or novel drug targets to combat Alzheimer's disease. (Delagarza,V. , 2003)
Novel therapies and there analysis
Lots of innovative work have been done and still under process to find the ideal therapy for Alzheimer's disease. It has been revealed in a study carried out in December 2005 that fresh sweet and sour cherries possess protective effect on neurons. Basis of this study was that cherries are rich source of antioxidants as anthocyanine, phenolic and flavonoids. These compounds destroy oxygen free radical and thus protect neurons in Alzheimer's disease.
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The task of study was to identify phenolics from various cultivars of sweet and sour cherries and evaluation of their effect on neurons. Phenolics were extracted from cherries of four sweet and four sour cultivars.
Table 1 (shows concentration of phenolics in mg Gallic acid equivalents per 100 gm of sweet and sour cherries and concentration of anthocyanins in mg cyanidin 3-glucoside equivalents per 100 gm of sweet and sour cherries.)
Type of cherry
92.1 to 146.8
30.2 to 76.6
146.1 to 312.4
49.1 to 109.2
Data obtained ( table 1 ) showed that concentration of total phenolics was higher in sour cherries as compared to sweet cherries as they possess higher concentration of anthocyanine and hydroxycinnamic acid. It was found by high performance liquid chromatography that anthocyanins such as cyanidin and peonidin were major phenolics. Result obtained was of significant importance and showed that cherries possess protective effect to neurons. (HJ et al.,2005) Montmorency cherry juice is now available as herbal supplement. It possess large amount of antioxidants. Various brands are manufacturing this product. "Cherry active cherry juice" product name is used by modern herbal (health brand) and cost of this product for 946 ml is 26.4£ in UK (ref through label). Cost of the product is not as higher as our current treatment but as their efficacy value is not sure in Alzheimer's patients so relying on this herbal supplement alone does not assure that person will not suffer from Alzheimer's diseases. Study showed that antioxidants were there in cherry but no information was provided that confirmed oxygen free radicals are key reason for Alzheimer's disease.
Another approach in 2007 targeted amyloid plaque by means of Î±Î² degrading protease. Task of study was to prove that Î±Î² degrading protease can be used to reduce amyloid plaque by means of ex vivo technique. Secreted form of Î±Î² degraded protease neprilysin was generated and it was introduced to brain of beta amyloid precursor protein transgenic mice which possess plaque deposition. One way analyses of variance, turkey post hoc comparison were used to analyse the data. Calculated comparison was significant for p < 0.05 (p value represents probability). Result showed that there was 72% reduction in plaque size at site of engraftment (p = 0.0269). It showed that Î±Î² degrading protease have potential to treat Alzheimer and this can be used as therapy. (Hemming et al.,2007 ) This result provided a platform to further focus on this approach. Further studies were done using the same approach on human subjects.
Recently in march 2010 phase 2 clinical trial was done for the drug semagacestat which inhibits gamma secretase (enzyme that leads to generation of beta amyloid and peptide deposit in plaque). It was a multicentric, randomized double blind, placebo controlled trial which involved dose escalation study. Thirty five subjects who all were suffering from mild to moderate Alzheimer's disease were randomized to placebo (n=10). To observe the effect of drug cerebrospinal fluid alpha beta pattern (AÎ²) were analysed by immunoprecipitation combined with MALDI-TOF (matrix assisted laser desorption/ionisation) mass spectrometry. For treatment group provided with dose 100mg, dose dependant increase was observed in AÎ² 1-14, AÎ²1-15 and AÎ² 1-16 by 57%, 74% and 21% respectively. For dose 140 mg treatment group increase in AÎ² 1-14, AÎ² 1-15 and AÎ² 1-16 was 35%, 30% and 67% respectively. Î‘Î² 1-40 and AÎ²1-42 pattern showed no change by this treatment. This study showed that AÎ² isoforms can be used as one of the sensitive biomarker which can help in monitoring the biochemical process in clinical trial.
In 2010 a study was done to evaluate the tolerability and efficacy of rivastigmine transdermal patch in patients who were suffering from mild to moderate Alzheimer's disease receiving concomitant memantine. Duration of study was 25 week. Randomized, prospective, open label, parallel group study design was chosen. Patients who were earlier receiving donepezil were provided with rivastigmine transdermal patch immediately or seven days withdrawal was followed for four weeks (core phase) and post hoc analysis was done. The selected dose was 4.6mg per 24 hours. Out of 135 and 126 patients who received rivastigmine with and without memantine, 122 and 118 patients respectively did pass the core phase however 90 and 86 patients respectively completed the study. Result showed that use of rivastigmine transdermal patch for patients on established memantine therapy was well tolerated with no significant increase in adverse effects compared with individual therapy. Alzheimer's disease level worsened in both groups and condition of patients was worst in those treated with memantine. (Olin et al., 2010)
Number of trail subjects in the study affects the result. All these novel approaches cannot be judged by their result only as there are several other factors which need to be considered. Alzheimer's disease trial should be for longer duration as new treatments effect cannot be illustrated by short duration trial with in two month or three month. Other effect of new drugs like side effects will be known by this. Numbers of trial subjects affect the trial result. High subject participation leads to increase in reliability of obtained data. On taking review of all previous research work done in Alzheimer's research showed that in most of clinical trial subjects are in short number. Due to ethical consideration and due to certain study protocol bias occurs and ultimately result gets affected by this. Subject withdrawal before the completion of trial is another issue. Investment over the research is another thing which affects the research. In UK £23 billion a year include annual cost to economy for dementia. Investment per person is £27,647. Annual investment for research is £50 million. On comparison with other diseases like cancer and heart disease where annual cost to economy is £12 billion for cancer and £8 billion for heart disease even then there research investment is £590 million and £169 million respectively that are much higher than Alzheimer's research cost. Taking incidence of Alzheimer's disease into consideration research work in quantity as well quality need to improve. Researches need more investment and more innovative ideas to eradicate this disease.
Alzheimer's disease is a life threatening condition emerging at a faster rate. Alzheimer's patients need mental support. Risk factors for this disease cannot be controlled. Early diagnosis of disease is essential to improve condition of patients by current therapies. Current treatments are not able to control the progression of this disease as exact cause of Alzheimer's disease is still not known. Novel therapies focusing different approach are emerging at a good rate but their efficacy is objectionable due to several factors as subject participation is less, ethical issues over use of placebo for patients suffering from severe disease and subject withdrawal in between the trail. We need to promote Alzheimer's research in order to get a better novel therapy then existing treatment. Novel therapies can give promising results as we are getting different approaches for treatment just the exact target need to be identified.