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ALZHEIMER'S DISEASE.
Term Paper ID:28723
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Essay Subject:
Damage to brain cells caused by neurodegenerative disorder. Symptoms, diagnosis, progression of disease, theories re: causes, treatment, identifying risk factors.... More...
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11 Pages / 2475 Words
11 sources, 15 Citations,
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Paper Abstract:
Damage to brain cells caused by neurodegenerative disorder. Symptoms, diagnosis, progression of disease, theories re: causes, treatment, identifying risk factors.
Paper Introduction:
Alzheimer=s disease is a neurodegenerative disorder which causes the destruction of certain brain cells resulting in a decline in mental functions. The damage occurs in the association area of the cerebral cortex, the hippocampus and the middle and temporal lobes, and result in a decreased concentration of the neurotransmitter acetylcholine (Sadovsky, 2000, p. 877). Alzheimer=s disease affects the memory, thinking, language, and behavior. It usually occurs in people over the age of 65, but can occur in those as young as 40 years of age. Symptoms can range from mild to severe, and when dementia occurs, patients are often placed in full-time residential care. It is estimated that about 10 percent of the population over the age of 65 suffer from Alzheimer=s disease (Alzheimer=s, 1999). Of these, between five percent and 10 perce
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West J. Alzheimer=s patientsusually have half as much ApoE in their spinal fluid, and it is thought therest is being deposited in the brain in these patients. Rohn used a monoclonal antibody 22C11, which binds to theextracellular domain of the human, rat, or mouse APP to study its role.Exposure of cortical neurons to 22C11 induced morphological changesincluding neurite degeneration, nuclear condensation, and internucleosomalDNA cleavage that were consistent with neurons dying by apoptosis. (1997). Several lines of evidence suggest that beta-amyloid is directlyinvolved in the neuropathology seen in familial and sporadic Alzheimer=sdisease. Chemical and structural changes in patients with Alzheimer=s interferewith a person=s ability to process, store and retrieve information.Symptoms of Alzheimer=s vary, and change with progression of the disease.The first symptoms are usually forgetfulness, memory loss and difficultyunderstanding written material (Alzheimer=s, 1999). The amount of spinal fluid tau protein,which is found in neurofibrillary tangles and is twice as abundant inAlzheimer=s patients, was normal in both groups. Symptoms can range from mildto severe, and when dementia occurs, patients are often placed in full-timeresidential care. Alzheimer=s disease affects the memory, thinking, language,and behavior. Personality and emotions change,and the patient may suffer from delusions, hallucinations, anxiety, andloss of motivation. Overall, the results showed that thebinding of a monoclonal antibody to APP initially triggers neuritedegeneration that is followed by capsase-dependent apoptosis in neuronalcultures and illustrates a property of this protein in neurons that maycontribute to the profound neuronal cell death associated with Alzheimer=sdisease. These mutations contribute to early onset Alzheimer=s(before age 65) and are inherited in an autosomal dominant fashion. Rohn, T. 2331-2342. Theyhave been given a battery of tests for cognitive and biological markers,including genetic testing, spinal fluid analysis, brain imaging, and bloodtests. Ballard, C., & O=Brien, J. Fam. (1999, November). Neurochem., 74, pp. A. Fam. A diagnosis of probable Alzheimer=scan be made after a medical history, physical exam and memory testing arecarried out. No evidence of linkage to the regionspanned by the chromosome 12 markers was found if familial Alzheimer=s isassumed to arise from the same genetic locus in all 53 families, butsignificant evidence for linkage was detected in the presence of locusheterogeneity using the admixture test. Tacrine, the earliest drug in this group, has only limitedbeneficial effects and a poor side effect profile, includinghepatotoxicity. The at-risk group had asignificantly increased prevalence of ApoE: 45 percent, compare to 8percent in the controls. News, 3 , p. (1998). O=Hara, R. Pract. Beta-amyloid is found in the cerebrospinal fluid of normal peopleand Alzheimer=s patients, so it is not an abnormal protein specific toAlzheimer=s - only its accumulation is. Mentally demanding work may deter Alzheimer=sdisease. A report in the British Medical Journal in 1998 summarized the datapresented at the 6th International Conference on Alzheimer=s disease thatyear on the genetic basis for Alzheimer=s (Edwardson and Morris, 1998).Evidence was presented at the conference that missense mutations in threegenes causes autosomal dominant forms of early onset Alzheimer=s, asdescribed above, and one genetic factor indisputably linked with the lateonset forms of Alzheimer=s that is the ApoE, also described above. 115-12 . ApoE appears to increase both thedeposition of A(beta) and the density of A(beta) plaques, all of whichindicate a central role for A(beta) in the pathogenesis of Alzheimer=sdisease. References Alzheimer=s Disease. No definitive treatment has yet emerged for thebehavioral and psychological signs in Alzheimer=s disease. Amulticenter study of 353 patients with mild to moderate Alzheimer=s diseaseshowed that those treated with galantamine maintained or improved theirscores on the Alzheimer=s Disease Assessment Scale during a one-yearperiod. Cognitively normal individuals with a familyhistory of Alzheimer=s disease have an increased prevalence of a geneallele associated with the disease, and have an abnormal level of beta-amyloid in the spinal fluid but the relationship between this finding andactual development of Alzheimer=s is unknown. Promising Alzheimer=s drug. This providesindependent confirmation of the existence of an Alzheimer=s diseasesusceptibility locus on chromosome 12 and suggests the existence ofAlzheimer=s disease susceptibility genes on other chromosomes. Update on Alzheimer=s disease: recent findingsand treatments. The correlation held true regardless of thesocial and physical demands of the job or the subject=s income, educationalattainment, and childhood socioeconomic status. Three groups of genetic mutations have been found to be associatedwith Alzheimer=s disease: mutations of the APP gene on chromosome 21, andseparate mutations of transmembrane protein genes on chromosomes 14 and 1,identified as presenilin 1 and presenilin 2, respectively (Weldon, Maggioand Mantyh, 1997). So far none of these hasbeen systematically replicated in experiments, so their significance inrelation to Alzheimer=s is unknown at present (Edwardson and Morris, 1998). An actual diagnosis of Alzheimer=s can only be made after death, sinceit entails dissection of the brain. Those patients with vascular risk receiving rivastigminedemonstrated less overall decline than patients without vascular risk. E., & Mantyh, P. 361-362. 18. The scale measure memory, language, orientation, and other aspectsof cognition. Although predictivefactors are not absolute, they are important for genetic counseling, and inproviding individuals with some means of preparing for the future. News, 3 , p. 1369. 813-816. Researchersbelieve that both actions lead to increased acetylcholine levels in thebrain. BMJ, 319, p. Alzheimer=s disease is a neurodegenerative disorder which causes thedestruction of certain brain cells resulting in a decline in mentalfunctions. Thefinding that staying mentally active may delay or prevent Alzheimer=s alsoprovides hope for those considered at-risk for the disease. At most, only half of late onset Alzheimer=s patients carryan ApoE allele. Because early intervention may prolong functioning in patients withAlzheimer=s disease, identifying risk factors has become important.Commonly identified risk factors include a family history of dementia,female, poor nutrition, atherosclerotic vascular disease, head injury,depression, engaging in fewer social activities, and lower occupationalattainment (Sadovsky, 2 ). Linkage analysis confirmed linkage tochromosome 12 with the strongest evidence at D12S96. 2379. That is, they have a family history of Alzheimer=s and show signsof the disease before age 65. Analyzing 193 Alzheimer=spatients and 359 controls, all over age 6 , nearly 6 percent of controlshad held jobs in managerial or professional specialties that were mentallydemanding, compared with only 25 percent of those with Alzheimer=s. New insightsinto the neuropathology and cell biology of Alzheimer=s disease.Geriatrics, 52, pp. Alzheimer=s is believed to occur due to the deathof neuronal cells, and there is considerable evidence that the alteredmetabolism of beta-amyloid precursor protein (APP) and accumulation of itsbeta-amyloid fragment are key features of Alzheimer=s disease. A prospective study is beingconducted on 76 healthy, cognitively normal at-risk individuals with afamily history of Alzheimer=s and 24 controls with no family history. It is estimated that about 1 percent of the populationover the age of 65 suffer from Alzheimer=s disease (Alzheimer=s, 1999). (2 ). One thing which has been found useful in protecting against developingAlzheimer=s later in life is working at a mentally demanding job (Moon,2 ). Individuals who were ApoE-positive had markedly lower levels of beta-amyloid in their CSF comparedwith ApoE-negative at-risk and control individuals. Ref. A whole string of genetic associations have been reported with lateonset Alzheimer=s, including polymorphisms in angiotensin convertingenzyme, antichymotrypsin, bleomycin hydrolase, butyrylcholinesterase, HLA,low density lipoprotein receptor related protein, various mitochondrialenzymes, and the presenilin 1 intronic mutation. Otherfeatures indicative of apoptosis were found: the formation of 12 - and 15 -kDa breakdown products of fodrin when cortical neurons were treated with22C11, but pretreatment of the neurons with the general capsase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp)o-methyl)-fluoromethyl ketone, prevented boththe morphological and the biochemical changes caused by 22C11. (2 ). Neuroleptic drugs are often used, but these have manyside effects, including parkinsonism, drowsiness, tardive dyskinesia,falls, accelerated cognitive decline, and severe neuroleptic sensitivityreactions. 138. Moon, M. Threeprospective studies have demonstrated significant benefits for Alzheimer=spatients who were at risk for developing vascular dementia withrivastigmine tartrate (Kumar, 2 ). A newer drug, rivastigmine, has a good side effectprofile, but requires more time for dosage titration than donepezil.Estrogen therapy increase acetylcholine concentrations and has antioxidantactivity, but proof of its ability to reduce the risk of Alzheimer=sdisease is inconclusive. (2 ). However,the normal function of APP is unknown (Rohn et al, 2 ). These researchers also showed that mouse immunoglobulin G and themonoclonal antibody P2-1, which is specific for the amino terminal end ofhuman but not rat APP, had no apparent effects on neuronal cells. The patients also maintained activities of daily living forthe year of the test. The hallmarks of Alzheimer=s pathology are extracellular plaquescontaining beta-amyloid, dystrophic neurites, activated microglia, reactiveastrocytes, and neuronal loss (Weldon, Maggio, and Mantyh, 1997). Also, there was no difference in response tothe scopolamine challenge: Alzheimer=s patients have a markedly increasedsensitivity to scopolamine, providing the basis for the use ofcholinesterase inhibitors in their treatment. T., Maggio, J. The feature these mutations have in common is that they all appear toincrease the productions of A(beta) peptide, specifically the 1-42 fragmentthat is especially prone to aggregation. Treating behavioral andpsychological signs in Alzheimer=s disease. It usually occurs in people over the age of 65, but canoccur in those as young as 4 years of age. Am. As brain function diminishes, the ability to talk,move or care for themselves is lost. Donepezil is a highly selective acetylcholinesteraseinhibitor that significantly improves cognitive scores with a better sideeffect profile. Syst., p. Clinical trials often lump together behavioral andpsychological signs, although they often have separate neurochemical andneurophysiological bases. (1999). If there is no other cause for the symptoms, then a diagnosisof Alzheimer=s is made. T. A strongcorrelation has been found between the amount of amyloid found in thebrains of Alzheimer=s patients at death and the degree of dementia observedin life. Rogaeva, E. Voelker, R. The participants will be tested every five to 1 years to see ifpositive markers are associated with development of the disease. As Alzheimer=s progresses,the person becomes disoriented and confused and can no longer remembermajor facts about him/herself and others. Antioxidants, includingselegiline, vitamin E and Ginkgo biloba have demonstrated some benefits inimproving cognition and delaying progression of Alzheimer=s, but outcomeshave been variable, making treatment recommendations difficult. Edwardson, J., & Morris, C. New treatment for patients with Alzheimer=sdisease. 877). Risperidone has been found to be beneficial in treating behaviordisturbances, and patients on cholinesterase inhibitors appear to have lesspsychotic symptoms. Managing the behavioral and psychological signs of dementia associatedwith Alzheimer=s is a major health care concern (Ballard and O=Brien,1999). Patients with and without vascular risk factors demonstratedstatistically significant improvement in global changes in cognitiveabilities, behavior and functioning, as well as significant clinicallymeaningful improvements in ability to perform activities of daily livingafter receiving rivastigmine for 26 weeks compared to controls who receivedplacebo. Kumar, V. Evidence for an Alzheimer=s diseasesusceptibility locus on chromosome 12 and for further locus heterogeneity.JAMA, 28 , pp. (2 ). JAMA, 283, p. Pract. The genetics of Alzheimer=sdisease: the number of genetic risk factors associated with the disorder isincreasing steadily. The precise location of theAlzheimer=s gene could not be determined, but includes the entire regionsuggested by earlier studies. Clin. Fam. Thissupports a role for 22C11-mediated apoptosis occurring by binding to APP,since preincubation of 22C11 with either purified APP or a syntheticpeptide (APP(66-81)) that contains the epitope for 22C11 significantlyattenuated neuronal damage induced by 22C11. A retrospectivecohort study of DNA data for six chromosome 12 genetic markers wasperformed on the 53 families, presorted for the presence or absence of theApoE allele among affected members. Galantamine is an acetylcholinesterase inhibitor,and also appears to act on nicotine receptors in the brain. W. (1998). While Alzheimer=s remains a severely debilitating ailment, and littletreatment is available at present, great strides have been made indeveloping screening tests for potential victims. Ofthese, between five percent and 1 percent have the familial form of thedisease. Anti-inflammatory drugs, including cyclooxygenase-2 inhibitors and steroids are under investigation. The mutations in APP, presenilin 1 and presenilin 2 allow for geneticscreening in suspected cases of familial Alzheimer=s disease with earlyonset for appropriate genetic counseling and support. Individuals at risk for Alzheimer=s disease have an increasedprevalence of certain biological markers, and may have subtle cognitivedeficits (Cheng, 2 ). Weldon, D. 48. (2 ). Cheng, G-S. Improvement was noted in dailyliving, behavior, cognition, memory, self-care and overall diseaseseverity. Working at a mentally challenging occupation from age 3 onwardscorrelated with a decreased risk of developing Alzheimer=s in a case-controlled study of 352 subjects studied at the University Hospitals ofCleveland Alzheimer=s Center. A monoclonal antibody to amyloid precursorprotein induces neuronal apoptosis. Phys., 62, p. Atbaseline testing, the younger at-risk group performed slightly worse onmost cognitive tasks than the older control group. It was also demonstrated thatselective application to compartmental cultures of hippocampal neurons of22C11 caused local neuritic degeneration that was prevented by the additionof GEF to the neuritic compartment. BMJ, 317, pp. Biomarkers, subtle cognitive deficits flagincreased risk for Alzheimer=s. The damage occurs in the association area of the cerebralcortex, the hippocampus and the middle and temporal lobes, and result in adecreased concentration of the neurotransmitter acetylcholine (Sadovsky,2 , p. (2 ). 614-62 . Also, priorincubation of cortical neurons with GSH ethyl ester (GEF), a cell-permeableform of GSH, resulted in complete protection from the 22C11 destruction,implicating an oxidative pathway in 22C11-mediated neuronal degeneration.This was further supported by pre-treatment of the neurons with buthioninesulfoximine, an inhibitor of gamma-glutamylcysteinyl synthetase,potentiated the toxic effects of 22C11. A recent study has also suggested a susceptibility gene forAlzheimer=s disease on chromosome 12 after an analysis of such a link in 53families with a history of the disease (Rogaeva, 1998). Recent memory isaffected more severely than longterm memory. Also,polymorphism of the (Epsilon)4 isoform of apolipoprotein E (ApoE)significantly increases the risk of both familial and sporadic Alzheimer=s. The main treatment for Alzheimer=s is the use of anticholinesteraseinhibitors, which increase the duration of acetylcholine action atsynapses. ApoE can be usedto predict risk of Alzheimer=s, but is not necessary or sufficient to causethe disease. Med., 172, pp. Another promising new drug is galantamine (Voelker, 2 ). J. It hasnow been found that three common allelic variants of ApoE exist - e2, e3,and e4 - encoded as a single gene locus on chromosome 19. Individuals with and without ApoE performedsimilarly overall in cognitive testing, but the ApoE-positive group didworse on a test for attention. There was nodifference between the at-risk group and the controls in behavioral changesor mood disturbances, brain volumes by magnetic resonance imaging, ororthostatic blood pressure. 22.
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