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ALZHEIMER'S DISEASE.
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Causes, effects, pathologic process, research, types, immune system, aluminum, treatment alternatives focusing on acetylcholinesterase inhibitors.... More...
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Paper Abstract:
Causes, effects, pathologic process, research, types, immune system, aluminum, treatment alternatives focusing on acetylcholinesterase inhibitors.
Paper Introduction:
Alzheimer's Disease/Senile Dementia of the Alzheimer Type:
The Role of Acetylcholinesterase Inhibitors
As the United States' population grows older, the chronic degenerative diseases of the elderly have become increasingly important. One condition that has received considerable attention is Alzheimer's disease, otherwise known as Senile Dementia of the Alzheimer Type (AD/SDAT). In recent years, researchers have begun to begun to elucidate the biochemical and physiological mechanisms which characterize this disorder. Moreover, despite the brain's inherent complexity and inaccessibility, several promising therapeutic modalities have emerged. Of these different agents, perhaps the acetylcholinesterase inhibitors exhibit the most potential. At the turn of the century, the average life expectancy in
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New York, NY: Alan R. G. Genetic defects identified in Alzheimer's disease. Atpresent, AD/SDAT costs the U.S. Alzheimer's disease--some biochemical clues. Anatomic and physiologic imaging of Alzheimer's disease. In addition, it has been found that nerve growth factoracts on the cholinergic neurons of the nucleus basalis. This is thought to occur throughnegative feedback autoreceptors. Other experimental evidence for an AD/SDAT cholinergic deficit hasinvolved biopsy samples. Liss, Inc.; 1989; pp. Furthermore, increased quantities of aluminum have been found inthe brains of AD/SDAT patients on autopsy. E., eds. Thetechnique, for example, has been found to demonstrate "selectively reducedresting glucose utilization" as compared with primary sensory and motorneocortical regions in living AD/SDAT patients. In: Iqbal, K.; Wisniewski, H. Intracellular aluminum mightsubsequently form stable linkages with either phosphoric groups or otherglutamic and aspartic residues. O.; Oxman, T. For the most part, AChE inhibitors can be taken orally. In addition, they may sufferfrom confusion, vascular factors, and impaired blood-brain barrierfunction. The acetylcholinesteraseinhibitors, for example, have demonstrated significant therapeutic value.It is very likely, however that Alzheimer's disease involves otherpathophysiologic mechanisms in addition to the cholinergic deficit. C. P. A. In fact, the "pathological hallmark" of Alzheimer's disease isatrophy in the nucleus basalis of Meynert (7:265-266). Finally, perhaps the most popular etiological argument forAlzheimer's disease involves the theories about aluminum. Thisinterface between the blood and the brain's extracellular fluid was firstobserved over 1 years ago. and abroad--hasfocused international attention on the mental disorder known as dementia.With each decade beyond 6 years, the relative number of persons at riskfor a dementing illness increases. Alzheimer's disease and related disorders. Approaches to the treatment of dementing illness. O.; Oxman, T. Neurochemical Research. Wisniewski, H. In: Emery, V. That makesAlzheimer's the nation's third most expensive illness, trailing only heartdisease and cancer. Ultimately, the various features of the BBB serve toregulate the composition of the interstitial fluid bathing the brain'sneurons and glia. The investigators were able to correlate thesedecreases in acetylcholine synthesis with the severity of patients'dementia (26:2 8-2 9). In: Emery, V. In addition to targeting acetylcholinesterase's active site, AChEinhibitors must also negotiate the blood-brain barrier (BBB). A second metabolic hypothesis proposed by Pettegrew et. L. During both normal andpathological aging, such protective structures as the blood-brain barrierappear to undergo alteration. Unfortunately though, these effectsdo tend to be short-lasting. Muchmore research will be needed before a drug, or a combination of drugs, isdevised that ameliorates all of the Alzheimer's symptoms. Moreover, despite the brain's inherent complexity andinaccessibility, several promising therapeutic modalities have emerged. These active-site-directed irreversible inhibitors, also knownas affinity labels, generally contain a highly "reactive electrophilicsubstituent that can generate a stable covalent bond with an active sitenucleophilic group (6:548-549)." Unfortunately though, as a result ofthese inhibitors' high reactivity, they tend to be either hydrolyzed byaqueous media and nonspecifically reactive with other protein molecules. Theproblem with treating the dementing syndromes, however, is that they tendto be exceedingly complicated (16:355). Implications of the blood-brain barrier and its manipulation. 1121-1154. Although trials involving the THA have proven controversial,it does appear to be of some therapeutic value: it may moderately improvememory and mildly improve cognition. In fact, the diseasewas familiar to the Hippocratic and Galen schools of physicians (29:2).Regardless though, it wasn't until about the early 2 th century that thedisease was fully described. Hakansson, L. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. In: Emery, V. Furthermore, little improvement has beendocumented for end-stage patients. 1-11.3 . Moreover,surviving neurons may attempt to reinnervate damaged areas. The spectrum of depressive dementia. Typically,covalent inhibitors achieve a loss of catalytic activity by chemicallymodifying an enzyme's active site amino acid residues. 87-1 6.12. Anticacetylcholinesterase activity of a series of N-t-alkylpyridinium compounds. The peptides, somatostatin,substance P, and neuropeptide Y, all seem to be decreased in Alzheimer's.Unfortunately though, the high polarity and low lipid solubility of thesesubstances tends to limit their passage through the blood-brain barrier.This makes it difficult to achieve therapeutic levels of the neuropeptides(8:1123-1125). Dugas, H. In this case, the activechemical moiety consists of a trimethylammonium group (i.e., N(CH3)3). 45:1391-1398; 1992, December.23. Chemistry in Britain. 199 , December. Thesedeposits form early in the disease process and result from abnormalprocessing of a 112-kDA glycoprotein amyloid peptide precursor (A4P). The "cholinergic deficit" in Alzheimer's became widely known duringthe 197 s. Research Resources Reporter. Unfortunately though, the molecular modificationsrequired by this technique tend to be extreme. Upon the discovery of Alzheimer's cholinergic deficit, manyparallels were drawn between the disease and Parkinson's. W.; Powers, R. Liss, Inc.; 1989; pp. M.; Wegiel, J.; Morys, J.; Bobinski, M. P.; Grundke-Iqbal, I.; Wisniewski, H. However--regardless of such hypotheses--it is alsopossible that, instead of being pathogenic, plaques are merely coincidentalto the pathophysiologic process (29:18). In: Emery, V. Overall though, AD/SDAT showssignificant genetic, clinical, and pathologic heterogeneity. Dementia: Presentations, differential diagnosis, and nosology. Its effect seems to be greatest when given"repeatedly up to seven times a day for several days" and/or in combinationwith lecithin (8:1131). 15:1239-1245; 199 . In AD/SDAT cortex, however, THA enhancesthe release of acetylcholine (18:1169). D.; Farrar, G.; Blair, J. In control cortical tissue, it has been observed that THA inducesa decreased release of acetylcholine. Over the last several decades, the acetylcholinesterase inhibitorshave found various applications. Likewise, it is thought that physostigmine also inhibits AChE throughits interaction with the enzyme's anionic active site (1 :8).Physostigmine and its derivatives contain an N(R)x group which is similarto the ammonium group found on acetylcholine. Lastly, patientswith primarily memory loss were observed to have no consistent asymmetry ofmetabolism (14:115). In general, the metal tends tooccur most predominantly in the neuritic plaques, neurofibrillary tangles,and within the nuclei of AD/SDAT affected cerebral grey matter. Such fragments could conceivably form the active conformation ofa drug molecule. Medical Hypotheses. Mechanism of action of cholinesterase inhibitors in Alzheimer's disease. Therapeutics of Alzheimer's disease for clinical and pre- clinical issues. As ß-peptidedeposits accumulate, they arrange into the ß-pleated sheet conformation ofamyloid fibrils. C.; Haroutunian, V.; Tsuboyama, G. M.; Winblad, B., eds. Dementia: Presentations, differential diagnosis, and nosology. In Alzheimer's disease, forexample, multiple neuronal systems die at variable rates resulting in theloss of target neurons, projecting neurons, and interneurons. Liss, Inc.; 1989; pp. P.; Malko, J. Although many different drugs have been considered in eachof these groups, the acetylcholinesterase inhibitors show the greatestpromise. O.; Oxman, T. New York, NY: Alan R. While most of the neuropathologic changes associated with AD/SDAToccur in the gray matter, the white-matter may additionally be affected.The introduction of high-resolution computed tomography (CT) in the 198 sdemonstrated pathological features now known as "leukoaraiosis." Suchpathologic findings generally include demyelination, axonal damage,gliosis, and hyaline arteriolosclerosis in the periventricular whitematter. 79-94.31. Itforms a "stereochemical fit" with the anionic site of theacetylcholinesterase enzyme (27:75). Australian Family Physician. Despite the other approaches to Alzheimer's treatment, most effortstowards therapeutic intervention have focused on pharmacology. (1988)holds that AD/SDAT could result from abnormal synthesis of membranephospholipids. Researchers have postulated that bybinding to amyloid fibrils, (1-antichymotrypsin creates a stable complex(3 :8 ). After being activated, suicideinhibitors (also known as kcat or "mechanism-based inhibitors) react withenzymes' active sites to produce irreversible inhibition. By 1989,however, the life expectancy for newborns had reached 75 years. A.; Levin, A. Thus far,however, only two cases of dementia have been reported in individuals knownto have long histories of occupational exposure to aluminum; it is not yetknown whether lesser exposures can cause neurotoxicity and dementia (21:61-62). Furthermore, AD/SDAT type II patients often present with CT-indicated leukoaraiosis (2:1 2). A.; McLachlan, D. Furthermore, there is evidence that, in addition toAlzheimer's, such a pathologic sequence of events may also occur in otherdiseases. However,as with lipidization, this method also has not yet been proven effective(2 :123). Preliminaryinvestigations suggest that the Phy analogue, heptyl-physostigmine, mayrepresent a considerable improvement over Phy. R. Bioorganic chemistry: A chemical approach to enzyme action. The threegeneral categories of pharmacologic agents employed for cognitiveenhancement include the cholinomimetic drugs, the nootropics, andmiscellaneous agents that act on catecholaminergic, peptidergic, aminergic,or unknown sites. 141-161.24. Liss, Inc.; 1989; pp. R.; Davis, P. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. Alzheimer dementia neuropathology. Molecular Pharmacology. Yet another well-known AChE inhibitor, physostigmine, has also beenused for several decades. 355-383.17. O.; Oxman, T. Iqbal, K.; Wang, G. (1993) found that various chemicalHUP alterations markedly affected its inhibitory potency toward humanbutyrylcholinesterase (1:555). IV. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. Dementia: Presentations, differential diagnosis, and nosology. The pathologic findingstypically include paired helical filaments in the form of neuritic plaquesand neurofibrillary tangles, as well as granulovacuoloar degeneration,amyloid angiopathy, loss of neurons, and atrophy of the brain. The analogues characteristically have higher lipophilicity,different body distribution, and altered pharmokinetics. Alzheimer's disease and related disorders. Tetrahydroaminoacridine (1,2,3,4-tetrahydro-9-aminoacridine), ortacrine, is a synthetic AChE inhibitor which was introduced in 1945. Blennow, K.; Wallin, A.; Gottfries, C. Theyare thought to be responsible for the primary degeneration of both theolfactory bulb and the associated cortex in people afflicted withAlzheimer's. In: Iqbal, K.; Wisniewski, H. M.; Winblad, B., eds. High liposome solubilitymight subsequently facilitate a drug's passage through the BBB. 7. CNS imaging and the brain barriers. At that time, a virtual revolution wasoccurring in histological method: major advances were being made in bothmicroscopic and staining technologies. Patterson, C.; Clarfield, A. Second edition. Moreover,all of the major components of the classical complement pathway occur inAlzheimer's disease brain tissue (3 :82). New York, NY: Alan R. Similar neurofibrillaryalteration is seen in other diseases. It remainsto be determined, however, whether these accumulations are a cause,contributor, or a consequence of Alzheimer's disease (29:16). In: Iqbal, K.; Wisniewski, H. The diagnosis is uncertain in 1 -5 % of the cases.Confirmation is generally made at autopsy. Clearly, there are many different acetylcholinesterase inhibitors.While the structure and action of each individual agent may be somewhatdifferent, enzyme inhibition generally occurs when an inhibitor moleculephysically or chemically blocks an enzyme's active site. In: Pardridge, W. 2. Using a silver-based staindeveloped by Bielschowsky in 19 2, Alois Alzheimer was able to demonstrateneuritic plaques and neurofibrillary tangles in the brain of a 51-year-olddemented woman. A.; Radebaugh, T. S. This approach, however,is limited by both technical and ethical difficulties (16:358). Clinics in Geriatric Medicine. Other symptomsinclude impairment of judgement, personality change, difficulty inlearning, and loss of language abilities. Dementia: Presentations, differential diagnosis, and nosology. Alzheimer's disease and related disorders. Muscarine is an alkaloid found in Amanita muscaria andother poisonous mushrooms. They have called for "international cooperationand support to conquer this disease (29:4)." AD/SDAT accounts for approximately 5 % of all cases of dementia; itis also the fourth or fifth most common cause of death. Such biochemical interactions couldeventually result in the intercellular or extracellular accumulation of"three-dimensional protidic edifices" such as amyloid deposits andneurofibrillary tangles. Once deposited, the amyloidsubsequently interacts with both neuropil and astrocytes to produce a broadspectrum of lesions. The drug has structural similarityto 4-aminopyridine. Despite their architecturethough, amyloid deposits are ultimately toxic to neurons (31:1-2). In contrast, senescence group analyzedcorrelative cliniconeuropathological studies (29:3). For the most part, suchlesions present as aphasia, agnosia, and apraxia. Laboratory diagnostic tests for Alzheimer's disease. Volume 2. However, many questionsregarding neurotrophic factor's usefulness in AD/SDAT remain unanswered. (1983) reported PET studies of AD/SDAT patientswith symptoms consisting predominantly of either aphasia or visuospatialdeficit. These include the classical, primitive, and diffuseplaque formations. In addition, MTF has also been shown to be quiteeffective. For example, the acetylcholineprecursors, choline and lecithin, have been administered in the hope ofraising acetylcholine levels. (1988) suggest that this mutation may be associated withthe presence of a proteoglycan receptor-type site and possible proteaseinhibition (8:1123). In addition,recent research has indicated that Huperzine A (HUP) binding to AChE may bedramatically affected by its molecular design. This demographic trend--both in the U.S. A second explanation for SDAT's heterogeneity may involve thedifferent capacities of individual patients to compensate for theirdisease. E., eds. When administered to humans, a "dose of 1 mg/kg of MTF givenorally produces an 8 % inhibition of plasma acetylcholinesterase, whichpersists for 2-3 days without inducing any significant side effects(8:1141)." Finally, the Huperzine series of alkaloid drugs were isolated byChinese pharmacologists at the Shanghai School of Medicine. In: Emery, V. Someresearchers have postulated that aluminum forms complexes with amino acidssuch as aspartic or glutamic acid. E., eds. Dementia: Presentations, differential diagnosis, and nosology. The dopaminedeficit observed in Parkinson's disease has been successfully treated usingL-DOPA. Thisobservation was thought to reflect a loss of the cholinergic pathwayslinking these structures to the nucleus basalis. This realizationmade it thus apparent that Alzheimer's ranked as a major health problem.As the years passed and the number of AD/SDAT victims grew, governmenteventually became involved. Amino acid-aluminum complexes may be involved in the neurologicdisturbance associated with Guam-Parkinson dementia as well. Moreover, this incidence is only expected to increase (12:679). The blood-brain barrier: Cellular and molecular biology. Young, J. Lastly, while the gene forone of the amyloid precursor proteins has been identified, its contributionto AD/SDAT etiology is not yet known. S.; Monjan, A. Hence, many younger people could bedeveloping neurophysiological signs of AD/SDAT without showing anydeterioration in cognitive functioning. The term, "temporoparietal symptoms," generally impliesdamage in both the temporal and parietal lobes. Despite its inherent difficulty though, suchwork has led to various treatments for AD/SDAT. Moreover, like 4-aminopyridine, THA blocks potassiumchannels in the synaptic membrane, thus prolonging the action potential andpossibly increasing neurotransmitter release (18:117 ). (1988) andKitaguchi et al. E.; Baynes, K. Huperzine Aand B come from the plant, Huperzia serrata. Deloncle, R.; Guillard, O. It occurs at the contact surface betweenblood plasma and the luminal capillary membrane. Of these, the cholinergic approaches are the mostdeveloped. Despite the apparentplausibility of such hypotheses though, they still lack convincing evidence(29:15). 6. In contrast,Alzheimer disease type II consists primarily of general cognitive symptoms,including memory disturbances. For example, the drug, pyridostigmine,was used during the Gulf War. 45:555-56 ; 1994, March. 95-1 7. Antiacetylcholinesterase activity and ring size in aromatic quaternary ammonium compounds. As a result of its structural similarity withacetylcholine, muscarine is able to compete with and block theneurotransmitter's action at acetylcholine receptors. According to Alzheimer's Association President, Edward Truschke,"Alzheimer's disease is draining the resources of this country and itscitizens at a greater rate than even we thought." It has been calculatedthat an average Alzheimer's patient diagnosed today will require over$213, in health care resources throughout their remaining years. New York, NY: Plenum Medical Book Company; 1989; pp. Thus, in effect,the inhibitors act like "molecular kamikazes," with the targeted enzymescatalyzing their own inactivation (6:552)." Obviously, such chemical systems could be applied to Alzheimer's.The physical and chemical characteristics of AChE itself might possibly beemployed to produce more effective inhibition. Liss, Inc.; 1989; pp. For the most part, the diagnosis is madethrough the collection of an appropriate history by excluding all othercauses of dementia (12:679). Certainly, AD/SDAT disease processes also affect theadrenergic, serotinergic, somatostatinergic, and glutamatergic, as well asother neuropeptinergic systems. New York, NY: Springer-Verlag; 1989. Yet another etiological mechanism for AD/SDAT involves abnormalproteins. 251-276. Foster et al. Indeed, some experts believe that AD/SDAT willeventually become the world's greatest socio-medical problem (4:1169). 16:1-4; 1992, September/October. Dementia: Presentations, differential diagnosis, and nosology. 1155-1167.16. Wisniewski, H. V. For example, while dementia afflictsonly 5% of people over the age of 65 years, about 15% of those over 8 suffer from the condition (4:1169). Heimark, R. For example, peptidelipidization involves small peptide fragments that can easily be made lipidsoluble. 38:1-4; 1992, May.----------------------- 28 Forexample, rather than causing Alzheimer's, observed immune responses couldalso result from some invading pathogen. Other treatment alternatives of AD/SDAT include "therapeuticneuropeptides" and hormonal approaches. M., ed. Thomas, J. Reactive microglial cells are known to vigorously express theMHC class II surface glycoprotein, HLA-DR. THA acts atmuscarinic and nicotinic receptors; this is evidenced by the fact that thedrug's action is precluded by both nicotinic and muscarinic receptorantagonists. A second approach to theBBB involves encapsulating drugs into liposomes. W.; Cummings, J. 3. As such processes continue,however, AD/SDAT gradually emerges as a "slowly progressive and globalencephalopathy (3 :87)." The early dementia typically interferes withpatients' ability to present themselves to the world in a "consistentcoherent manner" (17:1764). The ultimate result ofthis delayed enzyme regeneration is AChE inhibition. However, despite suchobservations, perhaps the main significance of the cholinergic deficit inAD/SDAT is that it provides researchers with a potentially effectiveapproach to treatment (25:1111). A., ed. McAllister, T. Cortical and subcortical dementias: Differential diagnosis. These variations on the original drug generally involvesome substitution of Phy's methylcarbamic group. O.; Oxman, T. Cowburn, J. Various metabolic alterations in affected neural tissuesmight include the following: (1) diminished glucose utilization; (2)reduced pyruvate dehydrogenase complex activity; and (3) abnormal oxidativemetabolism. Alzheimer's disease and related disorders. M.; Winblad, B., eds. E., eds. Numerous hypotheses have been proposed.Obviously, there is abundant evidence of a metabolic origin forAlzheimer's. over $82.7 billion annually in medicalexpenses, round-the-clock care, and lost productivity. K.; Kanof, P. In addition, the amyloid fibril-associated protein, tau, couldinitiate the formation of neurofibrillary tangles. Compounds of high polarity tend to have trouble gettingpast the barrier; they are obstructed by the endothelial cell's plasmamembrane. M.; Winblad, B., eds. By theyear 2 3 , it is estimated that over 5 million Americans will live to be65 (29:1). Howthis alteration affects membrane protein function and causes disease,however, remains to be determined (29:19). In addition, physostigmine analogues have been synthesized (i.e.,heptyl-physostigmine). This drug additionally interferes with nicotinicand muscarinic ligand binding (8:1145). Although some authors believe that neuritic plaque derives fromneurons, ultrastructural studies indicate that the amyloid fibrils areactually formed by microglia and pericytes. Some of themore common drugs include tetrahydroaminoacridine (THA) and physostigmine(Phy). This group, anexoethylidene moiety, and pyridone heteroatoms interact with AChE activesite amino acid residues. New York, NY: Raven Press; 1993; pp. al. Kirshner, H. E., eds. Consequently, various approaches have been proposed by whichpharmacologic agents may overcome the BBB. Ritchie, K.; Touchon, J. Then, from about the 194 s to the 196 s, a major divergence ofopinion emerged with regard to dementia etiology. It is,therefore, highly unlikely that the augmentation of one or twoneurotransmitter systems will alleviate patients' symptoms (16:358).Ideally, treatment should either arrest or reverse the disease processitself. L. In recent years, theelucidation of enzymatic structure and mechanisms has progressed at a rapidrate. Is it dementia? 1111-112 .26. Alzheimer's disease and related disorders. Aluminum as a pathogenic factor in senile dementia of the Alzheimer type: Ion specific chelation. (1981, 1983) also demonstratedthat Alzheimer's patients have relatively reduced levels of acetylcholinesynthesis (26:149). Eventually, in the196 s and 197 s, the ultrastructural studies revealed that the changescharacteristic of Alzheimer's (known then as presenile dementia) were thesame as those which occurred in senile dementia (2:95). For example, protease inhibitor, (1-antichymotrypsin, has beenassociated with amyloid deposits under various conditions (Alzheimer'sdisease, Down Syndrome, and aging). Thedrug readily crosses the blood-brain barrier to act on the central nervoussystem. A. The first signs may be difficult to detect.They usually involve subtle changes in a person's normal behaviors. Some of these apparent metabolic deficits, however, could alsoresult from diminished neuron populations. The studies of Tanzi et al. Pardridge, W. These patients often have late onsetdisease that lacks temporoparietal symptoms. Spectral nuclear magnetic resonance has demonstratedmembrane structural changes in both Alzheimer's and normal senescence. Suchbehaviors may range from routine daily activities such as housecleaning orauto maintenance, to changes in the way that a patient relates to others.Eventually, patients can experience a progressive and simultaneous declinein memory, orientation, and social skills (22:1391). Ofthese different agents, perhaps the acetylcholinesterase inhibitors exhibitthe most potential. M. Ashani et al. Lastly, the disease has alsobeen associated with the activation of various immune system cellularcomponents. 13-21.14. The studies, Ishii, Haga, and Shimizu (1975)and Ishii and Haga (1976), both observed IgG in senile plaques. This neuroanatomicstructure happens to be the brain's principal source of acetylcholine. 46-76.22. 8. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. In fact, the cells possessspecialized transport systems for the directional movement of specificsolutes (11:87-88). 9. Other AChE inhibitors include metrifonate,Huperzine A, and Huperzine B. The relationshipbetween abnormal tau phosphorylation and the formation of ß-amyloid,however, is incompletely understood (3 :87). Sage, M. Positron-emission tomography (PET),however, may be employed in the analysis of Alzheimer's (9:279-28 ). Peptide drug delivery to the brain. 1 :277-298; 1994, May.1 . One prominent feature of AD/SDAT is the fact that the observedstructural changes and cell death tend to occur in specific regions of thebrain. Ross, G. Journal of the American Chemical Society. It consists of five or six microglial cells and theiramyloid channels arranged into an amyloid star. This may make the nervous system morevulnerable to transmissible infective agents. Such substitutions mayinclude 1-16 carbon atoms, long alkylcarbamic groups, or dialkylcarbamicgroups. The normal physiologic function of theenzyme, acetylcholinesterase, involves the "rapid metabolic inactivation"of acetylcholine within the nerve synapse. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. D.; Davis, K. Santucci, A. M. However, the assumption that asingle transmitter is responsible for all of the Alzheimer's symptoms isoverly simplistic. Kruck, T. Perhaps the ideal anti-AChE drug would consist of a "suicideinhibitor." These toxic substrates typically require some type of chemicalactivation by the target molecule. 1 8-122.15. Target symptoms in thedisease include the following three clusters: (1) cognition; (2) overallfunction (such as activities of daily living); (3) quality of life. Dementia: Presentations, differential diagnosis, and nosology. 149:53-54; 1993.11. Alzheimer's disease and metal-containing glia. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. Neuronal death and dementia might then occur as aconsequence of complexed L-glutamic acid being unable to detoxify ammoniato produce glutamine. As with the other AChEinhibitors, HUP also contains an ammonium group. New York, NY: Oxford University Press; 1992.27. This fact led to several attempts at treating AD/SDAT through theaugmentation of cholinergic function. Multiple actions of THA on cholinergic neurotransmission in Alzheimer brains. "Ligand-receptor binding on glutamatergicneurons" and simple diffusion could then provide mechanisms by which thecomplexes could enter neurons (5:1239-1243). The primary function of thisglycoprotein is to present antigen to lymphocytes to stimulate an immuneresponse. The acetylcholinesterase inhibitor, metrifonate (MTF), is anorganophosphorous, slow-release agent with more enduring activity thaneither Phy or THA. M. The neuropathologic changes in AD/SDAT are primarily concentrated inthe gray matter regions of the brain. These decreased acetylcholine levels in AD/SDAT are particularlyrelevant because of the close association between the cholinergicneurotransmitters and memory functions. Additionally, theymay be bilateral, as well as localized in the temporoparietal areas. Perhaps the greatest therapeutic effect with thesedrugs is seen early in the course of Alzheimer's disease. For example, a criticalanalysis of several studies on Ache inhibitors found that--in double-blind,randomized, cross-over clinical trials--their therapeutic effects aresignificant and reproducible (8:1128). However, the physostigmine'sacyl (methyl carbamoyl) transfer to AChE serine residues involves a slowerrate of hydrolysis than occurs with acetylcholine. It may be that "progressive proteinalterations and the formation of abnormal filamentous structures inneuronal cytoplasm" represents a "nonspecific response of certain classesof human neurons to a variety of insults (3 :85)." Of the many other possible causative factors associated with AD/SDAT,one may be the immune system. M.; Winblad, B., eds. Milestones in the history of Alzheimer disease research. E. Furthermore, both drugs have fewer side effects thanphysostigmine or tacrine (8:1143). In: Neuwelt, E. Its effect on selective cognitive deficitstends to be inconsistent. Scientists are only just beginning to understand the processes of thebrain. Supplementum. O.; Oxman, T. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. The lesions may even accumulate for some time below a thresholdlevel before producing frank symptoms. In: Emery, V. It is known, for example, that the AChE ligand, acetylcholine, hasmuscarinic action. Various BBB anatomicfeatures give the barrier selective permeability. As the thirdmost abundant element in the earth's crust, the potential for aluminumexposure is virtually unlimited. Acta Neurologica Scandinavica. While various evidence seems toindicate that Phy, administered either orally or through intravenousinfusion, may improve memory, behavior, and neuropsychological testperformance (16:36 ). Heterogeneity in senile dementia of the Alzheimer type: individual differences, progressive deterioration or clinical sub-types? L. Not only does it exert anequivalent AChE inhibitory effect at much lower, less toxic doses, butheptyl-physostigmine may also have more long-lasting activity (8:1141). For the most part though, physostigmine'stherapeutic value is limited. Alzheimer's disease type I or "classical" Alzheimer'sis characterized by dominant temporoparietal symptoms, memory disturbances,a relatively younger age of onset, low frequency of vascular factors,normal blood-brain barrier function, and a low frequency of CT-indicatedleukoaraiosis. 1-51.25. The muscarine quaternary ammoniumhead group inhibits AChE by adsorbing on to its active site and hinderingthe approach of acetylcholine molecules (28:456). Interconnections betweenthe capillary endothelial cells, or complex tight junction belts, impose apassive, nonselective obstruction to solute exchange. Alzheimer's disease and related disorders. Of the two, Huperzine A may be themost potent. M. Liss, Inc.; 1989; pp. The two compoundsare therefore said to have bioisosterism: they contain functional chemicalgroups of similar molecular size and shape (6:8). By interfering withthis process, the Ache inhibitors functionally enhance synapticacetylcholine levels. E., eds. Baltimore, Md: The Johns Hopkins University Press; 1994; pp. HLA-DR may, therefore, be partially responsible for the presenceof large numbers of macrophages and infiltration by T-cells (both T-helperinducer and T-cytotoxic suppressor cells) in Alzheimer's affected tissue.Such phenomena could certainly represent a cell-mediated immune response.It is not known though, whether or not the response is pathogenic. Khachaturian, Z. Although the structural and physiological changes in AD/SDAT havebeen well characterized, the exact etiological mechanisms responsible forthe disease remain unclear. Oxman, T. Liss, Inc.; 1989; pp. C.; Alazraki, N. The future of Alzheimer's disease research. The fibrils then coalesce into plaque. Essentially, this consists ofesteratically cleaving the neurotransmitter (26:72). In experimental animals,these powerful AChE inhibitors have been shown to produce improvement inboth short-term and long-term memory. Mechanism of Alzheimer's disease: Arguments for a neurotransmitter-aluminum complex implication. The dementia generally correlateswith the extracellular deposition of a particular type of amyloid. Progressive aphasia and other focal presentations of Alzheimer disease, Pick disease, and other degenerative disorders. 5. 21:1762- 1768; 1992, December.18. In: Iqbal, K.; Wisniewski, H. Clinical aspects. In fact, decreased brain concentrations ofnorepinephrine, serotonin, and dopamine have all been reported amongpatients with primary degenerative dementia (7:266). M.; Winblad, B., eds. The inhibitors tendto be structurally and chemically reactive analogs of enzymes' normalsubstrates. These complexes might then be able tocross the blood-brain barrier. Alzheimer's disease is not a new phenomenon. Journal of Clinical Epidemiology. 3-18.2 . 1169-1178.19. In: Emery, V. In: Iqbal, K.; Wisniewski, H. Clinical subgroups in Alzheimer disease. At present, there is no laboratory diagnostic test available forAD/SDAT of either type (12:679). The early and accurate diagnosis of AD/SDAT has major significancefor clinical research (13:13). Giacobini, E.; Becker, R. Unfortunately though, its sideeffects include nausea and hepatotoxicity (16:36 ). Nordberg, A.; Nilsson-Hakansson, L.; Adem, A.; Lai, Z.; Winblad, B. In addition, muscarinic cholineric agonistshave been applied to mimic the action of acetylcholine on the postsynapticmembrane receptor (26:223). McLean, S. 679-687.13. This neurotrophicfactor could have a significant influence over neuronal survival, neuronalmetabolism, and neurotransmitter synthesis. In: Iqbal, K.; Wisniewski, H. They have beenfound to improve both memory and cognition. In 1976, researchers reported that choline acetyltransferase(the marker enzyme for acetylcholine synthesis) levels were decreased 7 %in the temporal cortex and hippocampus of AD/SDAT patients. Dementia: Presentations, differential diagnosis, and nosology. At the turn of the century, the average lifeexpectancy in the United States was only 47 years (19:3). With the discovery of leukoaraiosis, AD/SDAT was divided into twodifferent subtypes. alone, over 3 millionpeople have the most common dementing illness, Alzheimer's disease (2 :34). Present progress and future development in the therapy for Alzheimer's disease. O.; Oxman, T. New York, NY: Raven Press; 1991.21. Journal of the American Chemical Society. Some believed it to becaused by arteriosclerosis and stroke, while others saw it as a componentof normal senescence. O.; Oxman, T. Inquiries should determine the duration ofthe impairment, the mode of onset, as well as the rate and character of thedeterioration (21:47). K. For patients withsenile onset (over 65 years) life expectancy is 5 or 6 years less thanaverage; patients with presenile onset (under 65 years) typically live 15fewer years than their healthier counterparts. Emery, V. Quaternary ammonium compounds. Of the various experimental therapies for Alzheimer's, most havefailed to produce consistent or enduring results. Literature Cited 1. New York, NY: Alan R. Boundaries between normal aging and dementia. Giacometti, A. These characteristic PETchanges tend to occur early in the disease and persist. Of the differenttherapeutic options currently available, only fetal neural transplantationholds any promise for achieving such objectives. Strange, P. Processing at its C-terminus forms a 43-amino-acid, insoluble ß-peptide (also known as A4 peptide). In the U.S. The mechanisms by which neurotransmitters, their receptors,transmitter-receptor-effector complexes, and transmitter systems interactare all inherently complex. Alzheimer's disease and related disorders. The former group of researchers focused on theultrastructural and biochemical characteristics of the neurofibrillarytangles and neuritic plaques. Cell-cell adhesion molecules of the blood-brain barrier. Less well known AChE inhibitors includepyridostigmine bromide and m-(N,N,N-Trimethylammonio)-trifluoroacetone. Insome cases, Alzheimer's may also present focally in either hemisphere(14:115). 4. In addition, smallerlosses of choline acetyltransferase (CAT) were also observed in otherneuroanatomic regions. Substances movingbetween the neural capillary lumen and the brain's extracellular fluid musttherefore pass through--rather than between--the endothelial cells (24:2).This gives the endothelium an ability to actively exclude certain solutes,while facilitating the transfer of others. Thomas, J.; Marlow, W. The metal may occur in dust, drinkingwater, processed foods, cosmetics, and pharmaceutical preparations (15:1162-1163). Ashani, Y.; Grunwald, J.; Kronman, C.; Velan, B.; Shafferman, A. Hence, AD/SDAT may beviewed as a "major killer (2:95)." The pathologic processes in Alzheimer's are characteristicallyinsidious. Thirdly, acetylcholinesterase (Ache)inhibitors have been employed to prevent destruction of synapticacetylcholine. M.; Winblad, B., eds. New York, NY: Alan R. Despite physostigmine's problems, however, several Phy analogues havebeen synthesized. Genetic defects have been detectedin several families affected by a particularly severe form of AD/SDAT.Some investigators believe that a mutation on chromosome 21 may lead to abuildup of amyloid precursor (3:1). S. It has beenhypothesized that this variable course results from the fact that "randomdepletion of neurons may trigger more rapid deterioration in specificcortical areas whose relative weakness is genetically determined"(22:1396). Using normal control tissue obtained frompatients undergoing surgery, Sims et al. Moreover, like THA, physostigmine use has alsobeen associated with significant side effects (e.g., nausea). Diagnostic procedures for dementia. In: Emery, V. E., eds. The study found that the patients with aphasia had more lefthemisphere hypometabolism; whereas the patients with visuospatial deficitshad greater hypometabolism in their right hemisphere. In fact, it wasn't until industrialization beganto alter population trends that the subject became a major focus forresearch. In Alzheimer's, this generally involves the arrest of neuronaldamage as well as the promotion of neuronal regrowth. 7:75-77; 1964, January.28. In: Iqbal, K.; Wisniewski, H. Quaternary ammonium compounds. O.; Oxman, T. In recent years, researchers have begun to begun to elucidatethe biochemical and physiological mechanisms which characterize thisdisorder. E., eds. Of these, perhaps classical plaque is the mostrecognizable. Thisprecursor, which also occur in normal brain tissue, is thought to servesome kind of receptor function. New York, NY: Alan R. Role of tyrosine 337 in the binding of Huperzine A to the active site of human acetylcholinesterase. Despite Alois Alzheimer's clinical descriptions (19 7,1911), however, many years passed before people became interested in old-age associated dementia. 6:456- 457; 1963, July.29. Alzheimer's Disease/Senile Dementia of the Alzheimer Type: The Role of Acetylcholinesterase Inhibitors As the United States' population grows older, the chronicdegenerative diseases of the elderly have become increasingly important.One condition that has received considerable attention is Alzheimer'sdisease, otherwise known as Senile Dementia of the Alzheimer Type(AD/SDAT). R.; Turski, P. New York, NY: Alan R. Itsdegeneration results in abnormal cortical cholinergic function (23:141). Brain biochemistry and brain disorders. Collins, J. The Secretary of the United States Departmentof Health and Human Services established a special task force on AD/SDAT.In 1987, this effort produced a booklet published by the United StatesOffice of Technological Assessment: "Losing a Million Minds--Confrontingthe Tragedy of AD and Other Dementias." Currently, even the World HealthOrganization is involved.
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