Treatment Of Alzheimers Disease
Progressive changes in the molecular environment of neurons and Neurodegeneration has its implication in psychological functioning. Among the neurodegenerative diseases "Alzheimer's disease" produces an impairment of cognitive abilities that is gradual in onset but relentless in progression. Impairment of short-term memory usually is the first clinical feature, whereas retrieval of distant memories is preserved relatively well into the course of the disease. As the condition progresses, additional cognitive abilities are impaired, among them the ability to calculate, exercise visuospatial skills, and use common objects and tools (ideomotor apraxia). The level of arousal or alertness of the patient is not affected until the condition is very advanced, nor is there motor weakness, although muscular contractures are an almost universal feature of advanced stages of the disease.
Death, most often from a complication of immobility such as pneumonia or pulmonary embolism,usually ensues within 6 to 12 years of onset. The diagnosis of AD is based on careful clinical assessment of the patient and appropriate laboratory tests to exclude other disorders that may mimic AD; at present, no direct ante mortem confirmatory test exists. Alzhiemers are of different types ( Snell 1974):Early-onset Alzheimer'sLate-onset Alzheimer'sFamilial Alzheimer's disease (FAD)
This is a rare form of Alzheimer's disease in which people are diagnosed with the disease before age 65.Less than 10% of all Alzheimer's disease patients have this type. Because they experience premature aging, people with Down syndrome are particularly at risk for a form of early onset Alzheimer's disease. Adults with Down syndrome are often in their mid- to late 40s or early.
When symptoms first appear, younger people who develop Alzheimer's disease have more of the brain abnormalities that are associated with it. Early-onset Alzheimer's appears to be linked with a genetic defect on chromosome 14, to which late-onset Alzheimer's is not linked. Mutations of three genes, namely presenilin1, presenilin2, and amyloid precursor protein, are associated with Early Onset Alzheimer's disease. These genes in isolation do not cause Alzheimer's, however, mutations of these genes, can cause the disease.Changes in the brains of younger people affected by Alzheimer's disease are microscopic, involving twisting of nerve cells "known as neurofibrillary tangles" and formation of structures called plaques by a sticky protein called beta amyloid.
These plaques and tangles tend to damage healthy brain cells leading to shrinking and atrophy.A condition called myoclonus which causes muscle twitching and spasms is much more common in people with early onset than those who develop the disease later in life. These will all combine to make it very difficult for someone in the younger age group to continue to work or even take part in normal family life.Individuals with early-onset Alzheimer's disease will exhibit many of the sameÂ symptomsÂ as those whose disease appears later in life. MemoryÂ loss, confusion, personality changes and difficulties performing simple tasks are all very common symptoms and as the disease progresses emotional and social withdrawal is the norm.
Anyone who has this combination of symptoms should see a physician as soon as possible. Alzheimer'sÂ diagnosisÂ usually comes as a result of ruling out all other possibilities. The only way to biologically diagnose it is to examine brain tissue under a microscope, which is typically done only after death. (www.alzhiemerssociety.org)
This is the most common type of theÂ diseaseÂ affecting about 90% of all those with Alzheimer's. It affects people over the age of 65 with around 50% of all people over the age of 85 suffering from it. And the likelihood of developing late-onset Alzheimer's doubles every five years after the age of 65. Late-onset Alzheimer's disease may not be hereditary.
It is also known as "sporadic Alzheimer's" because it can affect any elderly person with no other common link other than the fact that they are all over 65.Late onset Alzheimer's causesÂ memory loss, confusion and difficulties in carrying out even the simplest tasks. Eventually a person will need constant care as they will be unable to look after themselves. On average people live roughly eight to ten years after diagnosis. Sometimes with sporadic Alzheimer's, because it affects people so late in life, another disease associated with old age could also be the cause of death. There is no cure and the jury is still out as to why some people get it and others don't.
It is indiscriminate of race, color, creed and lifestyle. In fact the only thing sufferers have in common appears to be old age. Unfortunately finding genes for incredibly complex conditions like sporadic Alzheimer's is a complicated business as there appears to be no link between who gets it and who doesn't.
So far researchers haven't come across one single common factor to determine the eventual development of late-onset Alzheimer's. What they have done, however, is identify a gene which may be a risk factor. Apo lipoprotein E (ApoE) is interesting in that it has both a negative and positive side in the development of Alzheimer's. The e4 type of the gene is found to carry a higher risk of Alzheimer's while the e2 type is believed to offer protection against it. Having this gene doesn't necessarily mean that a person will get Alzheimer's - what it does mean is that it may increase their risk.
Environmental factors, lifestyle and toxins can all play a part in weakening genes and making a person more susceptible to an illness. Sporadic Alzheimer'sÂ is a very difficult and complex disease for researchers because there is no real rhyme or reason to it. Until they can come up with an identifying factor other than age, there will be no cure. (Elbertyn 1984)Familial Alzheimer's disease (FAD):This is a form of Alzheimer's disease that is known to be entirely inherited. In affected families, members of at least two generations have had Alzheimer's disease.
FAD is extremely rare, accounting for less than 1% of all cases of Alzheimer's disease. It has a much earlier onset (often in the 40s) and can be clearly seen to run in families. In some extremely rare cases people in their 30s have been known to develop it. Histological, familial AD is practically indistinguishable from other forms ofÂ the disease. Deposits ofÂ amyloidÂ can be seen in sectionsÂ brainÂ tissue (visible as an apple-green yellow birefringence underÂ polarized light).
This amyloid protein forms plaques andÂ neurofibrillary tanglesÂ that progress through the memory centers of theÂ brain. Very rarely the plaque may be unique, or uncharacteristic of AD; this can happen when there is a mutation in one of the genes that creates a functional, but malformed, protein instead of the ineffective gene products that usually result from mutations. This type is genetically inherited due to a fault on chromosomes 1, 14 or 21.When this happens roughly 50% of the offspring of these sufferers will carry the genetic fault and all of them will go on to develop Alzheimer's.
Mutations in different genes the amyloidÂ precursorÂ proteinÂ (APP)Â geneÂ and the presenilin 1 and 2 (PSEN1 and PSEN2)Â genesÂ have been discovered in families with early-onset familial Alzheimer's disease. Taken together, theseÂ mutationsÂ only account for about 20-50% of familial Alzheimer's, indicating that other genes remain to be found in this disorder. The APP gene encodes the beta-amyloidÂ proteinÂ which accumulates abnormally in the brain in Alzheimer's disease. The protein products of the PSEN1 and PSEN2 genes interact withÂ proteinsÂ are involved in signalling processes within and between cells
Treatment of Alzheimer's Disease:
A major approach to the treatment of AD has involved attempts to augment the cholinergic function of the brain (Johnston, 1992). An early approach was the use of precursors of acetylcholine synthesis, such as choline chloride and phosphatidyl choline (lecithin).Although these supplements generally are well tolerated, randomized trials have failed to demonstrate any clinically significant efficacy.A somewhat more successful strategy has been the use of inhibitors of acetyl cholinesterase (AChE), the catabolic enzyme for acetylcholine. Physostigmine, a rapidly acting, reversible AChE inhibitor, produces improved responses in animal models of learning, and some studies have demonstrated mild transitory improvement in memory following physostigmine treatment in patients with AD.
The use of physostigmine has been limited because of its short half-life and tendency to produce symptoms of systemic cholinergic excess at therapeutic doses. Four inhibitors of AChE currently are approved by the FDA for treatment of Alzheimer's disease: tacrine (1,2,3,4-tetrahydro-9-aminoacridine; COGNEX), donepzil (ARICEPT), Rivastigmine (EXCELON), and Galantamine (RAZADYNE) (Mayeux and Sano, 1999).Tacrine is a potent centrally acting inhibitor of AChE (Freeman and Dawson, 1991). Studies of oral tacrine in combination with lecithin have confirmed that there is indeed an effect of tacrine on some measures of memory performance, but the magnitude of improvement observed with the combination of lecithin and tacrine is modest at best (Chatellier and Lacomblez, 1990).
The side effects of tacrine often are significant and dose-limiting; abdominal cramping, anorexia, nausea, vomiting, and diarrhoea are observed in up to one-third of patients receiving therapeutic doses, and elevations of serum transaminases are observed in up to 50% of those treated. Because of significant side effects, tacrine are not used widely clinically.Donepezil is a selective inhibitor of AChE in the CNS with little effect on AChE in peripheral tissues. It produces modest improvements in cognitive scores in Alzheimer's disease patients (Rogers and Friedhoff, 1998) and has a long half-life, allowing once-daily dosing.Rivastigmine and Galantamine are dosed twice daily and produce a similar degree of cognitive improvement. Adverse effects associated with Donepzil, Rivastigmine, and Galantamine are similar in character but generally less frequent and less severe than those observed with tacrine; they include nausea, diarrhoea, vomiting, and insomnia.
Donepzil, Rivastigmine, and Galantamine are not associated with the hepato-toxicity that limits the use of tacrine.An alternative strategy for the treatment of AD is the use of the NMDA glutamate-receptor antagonist Memantine. Memantine produces a use-dependent blockade of NMDA receptors. In patients with moderate to severe AD, use of memantine is associated with a reduced rate of clinical deterioration (Reisberg et al., 2003).
Whether this is due to a true disease modifying effect, possibly reduced excitotoxicity, or is a symptomatic effect of the drug is unclear. Adverse effects of memantine usually are mild and reversible and may include headache or dizziness.At present Dipeptidylpeptidase-9(DPP-9) enzyme are in current investigation for the treatment of AD.
OVERVIEW OF ACETYL CHOLINE ESTERASE:
Acetyl choline esterase is an enzyme involved in lysis of acetyl group and choline group in acetyl choline (CH3-CH2-(CO)2-CH2-CH2-N-(CH3)3. Acetylcholine (Ach) is a neurotransmitter in both the peripheral nervous system(PNS) and central nervous system (CNS) is one of many neurotransmitters in the autonomic nervous system(ANS),and the only neurotransmitter used in the motor division of the somatic nervous system. (Sensory neurons use glutamate and various peptides at their synapses.)
Synthesis and degradation:
Acetylcholine is synthesized in certain neurons by the enzyme choline acetyl transferase from the compounds choline and acetyl-CoA.
The enzyme acetyl cholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetyl cholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, thus causing paralysis of the muscles needed for breathing and stopping the beating of the heart.B)File:Acetylcholine.svg
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