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Alzheimer's Disease by: Adam Goodsell :

Alzheimer's Disease by: Adam Goodsell

History:

History Alzheimer's disease (AD) is a progressive degenerative disease of the brain and the most common form of dementia (Alzheimer's accounts for fifty to seventy percent of all cases of dementia). It affects memory and other cognitive abilities. Patients suffer from a gradual loss of memory and judgment, which causes the incapability of even simple tasks such as eating, and eventually death. Symptoms worsen over time and there is currently no cure.

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Alzheimer's was discovered by Alois Alzheimer in the year 1907, but it wasn't considered a major disease/disorder until the 1970's (Reger). In 1906 A. Alzheimer started by documenting a woman in her mid-fifties who began showing severe signs of memory loss and other cognitive abilities pertaining to memory, language, and social interaction. Eventually the unknown disease led to her death.

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After the woman's death, Alzheimer performed an autopsy on her brain. During the autopsy, using a silver staining technique that allowed him to see neurons, he found unusual formations in her brain. These formations are now known as senile plaques and neurofibrillary tangles. Alzheimer hypothesized that these legions were either the cause or effect (or a combination of the two) of the then unnamed Alzheimer's disease. At a later date, once more people were diagnosed with these symptoms and the diagnosis pointed to the symptoms named by Alois Alzheimer, the disease was named after him.

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This discovery was the first time anyone recognized the symptoms of Alzheimer's as anything more than consequences of aging. Even after Alzheimer's discoveries, the disease was still not a commonplace term, and dementia was still considered just another part of old age. It wasn't until the 1970's with the boom of neurological studies that Alzheimer's became well known and generally accepted as not just a general part of aging, but a disease that includes causes other than old age with old age being a major risk factor.

Pathology:

Pathology In the mid-1990's it was found that the main component of the plaques associated with Alzheimer's were caused by the biological breakdown of amyloid precursor protein (APP). After being synthesized by ribosomes, APP goes through post-translational processing where it is cleaved into smaller fragments by two enzymes, enzymes a and g secretase. When this occurs a harmless product, p3, is formed. Sometimes it is cleaved by b and g secretase, which produces either 40 or 42 amino acid chains. When the 42 amino chain, amyloid beta peptide, is created, it has a tendency to associate itself with other amyloid beta peptides. This association of amyloid beta peptides is thought to be responsible for the plaque formations between neurons of Alzheimer's patients.

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Under normal conditions, less than ten percent of amino acid chains formed via the enzymes b and g secretase were found to be the amyloid beta peptide responsible for the plaques. However, mutations in APP increase the production of the specific 42 amino acid chain. This increase in production of amyloid beta peptide becomes too much for the body to remove. When the body is unable to remove this peptide, plaques form between neurons. This prevents messages from being transmitted. Because of this association between APP and Alzheimer's, research on APP has been consistently growing. Yet, even with intense research, the purposes/biological functions of APP are not very well understood. Researchers still do not know why the body goes through the process of potentially producing such a harmful amino acid chain.

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There has, however, been recent research done in 2009 that suggests some sort of physiological functions of APP (Cristina). Researchers T. Südhof and X. Cao started studying the cytoplasmic tail of APP and its interactions with proteins Fe65 and Tip60 in the function of activating transcription. Two models were formed, with the latter having more support. In the first model, APP grabs onto Fe65 which prevents it from entering the nucleus and binding with Tip60 thus preventing the activation of transcription. When APP is split, Fe65 is released into the nucleus, binds to Tip60, and activates transcription. In the second, more data supported model, the cytoplasmic tail of APP is directly responsible for the activation of transcription. Although this recent information doesn't further explain how Alzheimer's disease is caused, it does give some sort of hypothesis as to what the purpose of this potentially deadly process is and thus gets us closer to the cure for Alzheimer's.

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The APP/X11/FE65 protein network.

Symptoms :

Symptoms Alzheimer's can be broken down into three different types: late-onset, early-onset, and Familial Alzheimer's disease (FAD for short and also known as sporadic Alzheimer's disease). These three types vary by the age they affect and whether or not they are hereditary. Some cases occur before age sixty five, while others that are more common occur after. Late-onset Alzheimer's disease is the most common form of the disease and accounts for approximately ninety percent of cases. It usually occurs after the age of sixty-five and almost half of the population over the age of eighty-five develop it. It may or may not be hereditary.

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Early-onset Alzheimer's occurs in individuals before the age of sixty-five and is a rare form of the disease, accounting for less than ten percent of all Alzheimer's patients. Even more brain abnormalities are associated with early-onset Alzheimer's in young people than other forms of Alzheimer's. A trait found more commonly in early-onset Alzheimer's than in late-onset is muscle twitching and spasms, a condition called myoclonus. Also, due to premature ageing, people with Down syndrome are predisposed for early-onset Alzheimer's disease. Familial Alzheimer's disease is the rarest form of the disease, occurring in less than one percent of all Alzheimer's cases. FAD is the form of the disease that is known to be completely inherited. It also has an early-onset like early-onset Alzheimer's disease. This form of the disease can be clearly traced through the family.

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Alzheimer's disease can also be broken down into different stages of its progression. It is a chronic and progressive disease. This means that as more and more of the brain is damaged, symptoms increase in severity. Each individual doesn't develop every symptom of every stage. The following three stages are generalizations of the progression of Alzheimer's.

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In Alzheimer's earliest stages, symptoms are mild (Bupa). Common symptoms are mild forgetfulness and/or problems coming up with the right words. Family and friends may notice small changes in behavior. Loss of interest in life's many activities and mood swings are also common in early stages. It may be difficult for the patient to concentrate and he/she may have trouble with decision making. This stage usually lasts two to four years.

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During Alzheimer's middle stages the disease progresses (Bupa). This is the longest stage with the average length being two to ten years. Memory loss and trouble with speech get worse. New people and surroundings become confusing. The patient can have trouble with recognizing previously well-known family and friends. Obvious changes in normal behavior occur such as mood swings (unprovoked aggression, depression, etc.). Common tasks such as laundry, shopping, and dressing are made harder. Sense of time and place become distorted.

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In the late stages of Alzheimer's disease, the patient is usually completely dependent on a caretaker (Alzheimer's Association). There is difficulty eating. Incontinence occurs. Other motor skills such as walking, writing, and even sitting up on one's own become impossible. At its latest stages, even simple functions like swallowing become difficult or impossible. Total loss of time, of association with others, and of recognition of one's self occur. Because there is no cure for AD, this final stage, which usually lasts one to three years, ends with the death of the patient.

Treatment:

Treatment Without a cure for Alzheimer's disease, for the most part, the symptoms themselves must be treated instead of the disease itself. Even when addressing the symptoms, there are few treatments available and how well they work is questionable. One treatment for Alzheimer's that doesn't just treat the symptoms, but is used as a preventative measure, is the use of non-steroidal anti-inflammatory drugs (NSAIDs) in protecting individuals with the ε4 allele of the apolipoprotein E (APOE ε4) . This allele predisposes the individual for late-onset/familial Alzheimer's.

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The mechanism by which NSAIDs work against Alzheimer's is not fully understood. It could be their anti-inflammatory effects, or their ability to interfere with the β-amyloid cascade. In two long term studies done using NSAIDs, the Alzheimer's patients did not improve. But in another study, treatment was started earlier. In the latter study, patients previously exposed to NSAIDs were protected from onset of Alzheimer's disease by si xty-seven percent compared to the placebo. It was hypothesized that NSAIDs were only beneficial when used in the most early stages of Alzheimer's patients with APOE ε4. This is due to the prevention of initial deposition of β-amyloid (Imbimbo).

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Another Alzheimer's treatment is the use of cholinesterase inhibitors. Even though Alzheimer's is usually associated with deficits in a number of cerebral neurotransmitters, it is thought that the cognitive deficits attributed to Alzheimer's can be primarily associated with the degeneration of cholinergic neurons in the cortex and hippocampus. This deficit results in deficits of cholinergic neurotransmission. Also, these deficiencies may be associated with the formation of the plaques and tangles associated with Alzheimer's (Drug Ther Perspect).

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Because of these deficits and associations, cholinesterase inhibitors (ChEI) are used in the treatment of Alzheimer's patients. There are two types of cholinesterase enzymes, of which acetylcholinesterase has been focused on in treatments for Alzheimer's. This focus is due to the fact that this specific cholinesterase enzyme, acetylcholinesterase, is involved in synaptic function (a chemical communication between two cells that are next to each other). Donepezil is an example of a cholinesterase inhibitor. It is a noncompetitive cholinesterase inhibitor specific for acetylcholinesterase. Its purpose in inhibiting this enzyme is to prevent the breakdown of acetylcholine. Acetylcholine is a chemical messenger important for learning and memory use. By keeping acetylcholine levels high, communication among nerve cells functions properly. Cholinesterase inhibitors only work for about fifty percent who take them, and only delays the worsening of symptoms for six to twelve months (Alzheimer's Association). There has been, however, a study done in 2010 that showed a positive correlation between ChEI treatment and pulmonary disorders in those over the age of eighty (Helou R). Cholinesterase, along with memantine, are the two main drugs approved by the FDA for treatment of Alzheimer's.

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Another common treatment for Alzheimer's, memantine, is an uncompetitive low-to-moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist. Memantine works by regulating one of the brain's chemicals associated with information processing, storage, and retrieval. This chemical is glutamate. Glutamate functions by triggering NMDA receptors to allow certain amount of calcium into nerve cells which aids in information storage. When there is an excess of glutamate (as is found in Alzheimer's), NMDA receptors are over stimulated. This triggers the release of too much calcium into nerve cells and leads to the disruption and death of the cells.

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Memantine acts by partially blocking the NMDA receptors in order to prevent excess calcium in nerve cells.

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Some studies question the effectiveness of memantine. However, a recent, six month study done in 2010 showed positive results. ADL score was used to test patient's abilities to perform basic functions such as eating and bathing, and instrumental functions such as using a telephone and finding belongings. Memantine-treated patients were found to have less of a decrease in their ADL score than those given a placebo (Winblad B.).

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Many difficulties arise when studying Alzheimer's for new treatments or even a cure. Alzheimer's develops slowly which means patients must be constantly watched. Symptoms may appear late in the process of the disease. By this time in the disease, the early stages can no longer be studied and patients already have significant damage to brain cells. Many symptoms overlap with symptoms of other diseases. This leads to inaccurate diagnoses. When there are inaccurate diagnoses, clinical trials are distorted. For example, if ten percent of patients in the trials are misdiagnosed, then they are obviously not likely to respond to the treatment given to them. Even this ten percent fault in accuracy is enough to sway a trial away from showing statistically significant benefits.

Diagnosis:

Diagnosis In diagnosing this fatal disease, there is no single test. Instead many factors are taken into place in determining the cause of the patient's dementia. Doctor's review the patient's medical history and family medical history. The medical history is reviewed in order to see if Alzheimer's runs in the family. If it does run in the family, there is a greater chance of the patient also having the disease. Also involved in diagnosing Alzheimer's is the use of mental status tests, the most common being the mini-mental state examination (MMSE). This test, given by health professionals, requires the patient to answer a series of questions that test everyday mental skills.

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The MMSE may include questions about things such as the year, season, day of the week. It includes other things such as repeating a common phrase after the examiner, copying a picture of two interlocking shapes, counting backwards, spelling a word backwards, and following other instructions. The test is out of thirty and anything below a twenty-five suggests some sort of dementia. On average, Alzheimer's patients decline two to four points a year.

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Another popular mental status test is the mini-cog. It requires two tasks of the patient. In the first task the patient is required to do some sort of remembering or memorization and then repeating the names of three common objects. In the second task the patient is required to draw a clock with all twelve numbers in the correct places. He/she then has to place the hands of the clock in the correct positions according to a time stated by the examiner. Besides the two tasks in the mini-cog, the patient is also evaluated for their sense of well-being in order to determine if the symptoms of Alzheimer's were caused by depression or other mood disorders instead of Alzheimer's.

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Patients also undergo physical exams in order to test for other diseases that may be causing memory issues, irrational thinking, focusing trouble, and other dementia symptoms. The patients are asked about their diet and nutrition. They then have their blood pressure checked and blood/urine samples collected. Also the examiner will listen to the patient's heart and lungs. These all test for other possible causes of dementia symptoms such as infections, excessive drinking, anemia and other malnutrition, diabetes, heart issues, and many others.

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Patients also undergo a neurological exam and brain imaging. Their reflexes, speech, eye movement, muscle tone, sense of feeling, and coordination are tested. The purpose of this is to assess the function of the brain and nervous system in order to attempt to diagnose brain disorders other than Alzheimer's. Brain imaging such as Structural imaging and Functional imaging is a fairly recent technology in aiding the diagnosis of Alzheimer's. Structural imaging uses the MRI and less commonly computed tomography (CT) to provide information about the shape and position of brain tissue. Functional imaging uses techniques such as the positron emission tomography (PET) and functional MRI (fMRI) in order to help the examiner understand how well cells in different regions of the brain are functing. The way these tests work is by showing how much sugar or oxygen is used in the cells.

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In a 2009 study, twenty-one Alzheimer's patients and twenty controls were used to study PIB and PET imaging (Tolboom). The PIB imaging tests of the patients were rated as either normal or AD without the raters knowing which patients the images came from. The PIB tests were also compared with the PET tests. There was much agreement between readers of the tests on which patients they came from and their accuracy. Overall, PIB showed to be a highly accurate testing method.

Conclusion:

Conclusion Alzheimer's is a progressive degenerative disease that was discovered in 1907 but wasn't intensely studied until the 1970's. Over time patients lose their ability to remember how to do even the simplest tasks and life on their own becomes impossible. Because there is no cure available, the disease eventually leads to the patient's death. There are however treatments that slow down the process of Alzheimer's such as, NSAIDs, ChEI, and memantine. Diagnosis can be difficult which leads to problems in finding a cure for Alzheimer's. Recent studies on APP, however, provide hope in eventually finding the exact causes and a cure for Alzheimer's disease.

Works Cited:

Works Cited Alzheimer's Association. "Alzheimer's Association - Standard Treatments." Alz.org . 12 June 2010. Web.06 Dec. 2010. Alzheimer's Association. "Alzheimer's Disease Stages - Dementia Types - Alzheimer's Symptoms - Prevention." Heartspring.net . Alzheimer's Association, 6 Aug. 2004. Web. 06 Dec. 2010. Bupa. "Alzheimer's Disease." Bupa.co.uk . Bupa Health Information Team, Apr. 2009.Web. 5 Dec. 2010. Brooks, Larry, and David Loewenstein. "Assessing the Progression of Mild Cognitive Impairment to Alzheimer's Disease: Current Trends and Future Directions." Alzres.com . Alzheimer's Research & Therapy, 28 Feb. 2010. Web. 05 Dec. 2010. Cristina, Tang. "Regulation of Gene Expression: A New Role For an Alzheimer's Protein?" JYI.org . The Journal of Young Investigators, 2009. Web. 5 Dec. 2010. Doody, Rachelle. "Correction: Predicting Progression of Alzheimer's Disease." Alzres.com . Alzheimer's Research & Therapy, 14 Feb. 2010. Web. 06 Dec. 2010.

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Drug Ther Perspect. "Donepezil for the Management of Patients With Alzheimer's Disease: How Cholinesterase Inhibitors Work." Medscape.com . Adis Data Information BV, 17 Nov. 2001. Web. 4 Dec. 2010. Helou R, and M Rhalimi. "Cholinesterase Inhibitors and the Risk of Pulmonary Disorders in Hospitalized Dementia Patients." Journal of Population Therapeutics and Clinical Pharmacology = Journal De La Thérapeutique Des Populations Et De La Pharamcologie Clinique . 17.3 (2010): e379-89. Imbimbo, Bruno P., Vincenzo Solfrizzi, and Francesco Panza. "Are NSAIDs Useful to Treat Alzheimer's Disease or Mild Cognitive Impairment?" Ncbi.nlm.nih.gov . Front Aging Neurosci, 8 Apr. 2010. Web. 3 Dec. 2010 Reger, Beth. "Alzheimer's Disease: A Brief History and Avenues for Current Research." JYI.org . The Journal of Young Investigators, Aug. 2002. Web. 07 Dec. 2010. Tolboom, Nalleke. "Molecular Imaging in the Diagnosis of Alzheimer's Disease: Visual Assessment of PIB and FDDNP PET Images -- Tolboom Et Al. 81 (8): 882 -- Journal of Neurology, Neurosurgery & Psychiatry." Jnnp.bmj.com . J Neurol Neurosurg Psychiatry, 11 June 2010. Web. 04 Dec. 2010. Winblad B, et al. "Memantine Benefits Functional Abilities in Moderate to Severe Alzheimer ' S Disease." The Journal of Nutrition, Health & Aging . 14.9 (2010): 770-4.

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