alzheimer's disease ad, apolipoprotein e poe, donepezil, tacrine, tau
A Pithadia. Pathophysiology and pharmacotherapy of Alzheimer's disease (AD). The Internet Journal of Pharmacology. 2007 Volume 6 Number 1.
Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain... Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.
Alzheimer's disease is characterized by the development of senile plaques and neurofibrillary tangles, which are associated with neuronal destruction, particularly in cholinergic neurons. Drugs that inhibit the degradation of acetylcholine within synapses are the mainstay of therapy. Donepezil, rivastigmine, and galantamine are safe but have potentially troublesome cholinergic side effects, including nausea, anorexia, diarrhea, vomiting, and weight loss. These adverse reactions are often self-limited and can be minimized by slow drug titration. Acetylcholinesterase inhibitors appear to be effective, but the magnitude of benefit may be greater in clinical trials than in practice. The drugs clearly improve cognition, but evidence is less robust for benefits in delaying nursing home placement and improving functional ability and behaviors. Benefit for vitamin E or selegiline has been suggested, but supporting evidence is not strong. Most guidelines for monitoring drug therapy in patients with Alzheimer's disease recommend periodic measurements of cognition and functional ability. The guidelines generally advise discontinuing therapy with acetylcholinesterase inhibitors when dementia becomes severe.
In 1996, approximately 4 million people in the United States were clinically diagnosed with AD; this figure is expected to triple in the next 50 years. Women are more affected than men at a ratio of almost 2:1 due in part to the larger population of women who are over 70; however, the prevalence is still higher in women even after statistical correction for longevity. Age is another important risk factor. At the age of 60, the risk of developing AD is estimated to be 1%, doubling every five years to reach 30-50% by the age of 85. Other reported risk factors include lower levels of intelligence and education (defined as primary education only), small head size, and a family history of the disease.A recent meta analysis of head injury, as a risk factor for Alzheimer's disease, seems to establish that in males at least there is a definite association.
Genetic risk factors are clearly involved in the pathogenesis of AD. In particular, the gene for Apolipoprotein E (ApoE) on chromosome 19 has gained much recent attention. ApoE is a protein modulator of phospholipid transport that may have a role in synaptic remodeling. ApoE has three common alleles, ApoE epsilon (e) 2, 3, and 4 that are expressed in varying amounts in the normal individual. It is the ApoE e4 genotype that is associated with the risk of AD. Postulated mechanisms include amyloid deposition and abnormal tau phosphorylation, a major component of neurofibrillary tangles. Unlike the chromosomal mutations that are responsible for early onset AD, the presence of ApoE in itself does not cause AD nor does it guarantee that the carrier will develop any clinical manifestations. Therefore, at this point in time it should not be used as a screening tool for normal individuals who are concerned about developing the disease.
The classic neuropathological findings in AD include amyloid plaques, neurofibrillary tangles, synaptic and neuronal cell death. Granulovacuolar degeneration in the hippocampus and amyloid deposition in blood vessels may also be seen on tissue examination, but are not required for the diagnosis
Although amyloid plaques or
Neurofibrillary tangles are paired helical filaments composed of tau protein which in normal cells are essential for axonal growth and development. However, when hyper-phosphorylated, the tau protein forms tangles that are systematically deposited within neurons located in the hippocampus and medial temporal lobe, the parieto-temporal region,and the frontal association cortices leading to cell death.
Neuron and Synapse Loss
Areas of neuronal cell death and synapse loss are found throughout a similar distribution pattern as the neurofibrillary tangles, but greatly affect neurotransmitter pathways. The death of cholinergic neurons in the basalis nucleus of Meynert leads to a deficit in acetylcholine (Ach), a major transmitter thought to be involved with memory. In addition, serotonergic neurons in the median raphe and adrenergic neurons in the locus coerulus lead to deficits in serotonin and norepinephrine respectively.
Genetic mutations in chromosomes 21, 14, and 1 have been shown to cause familial early-onset AD. Inherited in an autosomal dominant pattern, the chromosomal mutations account for less than 5% of all cases and result in the overproduction and deposition of Aß. 6 Chromosome 21, which codes for APP, was first evaluated for an association with AD when Down's syndrome patients with the trisomy 21 aberration were observed to develop dementia in the fourth decade. Mutations in presenilin 1 (PS-1) on chromosome 14 and presenilin 2 (PS-2) on chromosome 1 also cause AD and are responsible for the majority of familial early-onset cases.
The exact role of inflammation in the pathogenesis of AD is still controversial. Although some studies have been able to demonstrate the presence of activated microglia (a marker of the brain's immune response) in patients with probable AD, a number of prospective clinical trials evaluating the use of drugs targeting various aspects of the immune system such as prednisone, hydroxycholoroquine, and selective COX-2 inhibitors have only been able to demonstrate marginal benefits at best. 7
While some studies have suggested a neuroprotective role for non-steroidal anti-inflammatory drugs a recent large study of 351 patients revealed that these medications did not slow progression and cognitive decline in established mild to moderate Alzheimer's disease.
Symptoms and stages
Common early symptoms of Alzheimer's are confusion, disturbances in short-term memory, problems with attention and spatial orientation, personality changes, language difficulties, unexplained mood swings.
It is important to understand that Alzheimer's disease does not affect every patient in the same way. The stages listed below represent the general progression of the disease.
Stage 1: Early in the illness, Alzheimer's patients tend to have less energy and spontaneity, though often no one notices anything unusual. They exhibit minor memory loss and mood swings, and are slow to learn and react. After a while they start to shy away from anything new and prefer the familiar. Memory loss begins to affect job performance. The patient is confused, gets lost easily, and exercises poor judgment.
Stage 2: In this stage, the Alzheimer's victim can still perform tasks independently, but may need assistance with more complicated activities. Speech and understanding become slower, and patients often lose their train of thought in mid-sentence. 4 They may also get lost while traveling or forget to pay bills. As Alzheimer's victims become aware of this loss of control, they may become depressed, irritable and restless. The individual is clearly becoming disabled. The distant past may be recalled, while recent events are difficult to remember. Advancing Alzheimer's has affected the victim's ability to comprehend where they are, the day and the time. Caregivers must give clear instructions and repeat them often. As the Alzheimer's victims mind continues to slip away, the patient may invent words and not recognize familiar faces.
Stage 3: During the final stage, patients lose the ability to chew and swallow. The very essence of the person is vanishing. Memory is now very poor and no one is recognizable. Patients lose bowel and bladder control, and eventually need constant care. They become vulnerable to pneumonia, infection and other illnesses. Respiratory problems worsen, particularly when the patient becomes bedridden. This terminal stage eventually leads to death.
In 1984 the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Diseases Association (NINCDS-ARDA) established diagnostic criteria designed for research purposes and clinical definition. Now recommended by the American Academy of Neurology (AAN) for the diagnosis of AD, this classification is divided into definite, probable, and possible AD. (See AAN national guidelines for the diagnosis and management of Alzheimer's disease, the contents of which are summarized in the following paragraphs.)
In addition to histopathological confirmation, definite AD requires the clinical finding of dementia as determined by the Mini-Mental Status Exam (MMSE) or other standardized neuropsychological testing; the exam must demonstrate deficits in two or more areas of cognition with progressive memory loss in the absence of delirium.
Probable AD is the clinical determination of dementia as described above and is supported by the findings of impaired activities of daily living, loss of specific cognitive functions such as language and motor skills, and a family history.Other clinical findings that support the diagnosis in patients with advanced AD are myoclonus, gait disorder, and increased muscle tone. Possible AD is considered when there is variation in the onset, presentation, or clinical course of the dementia and when a second brain disease or systemic disorder is present. Clinical factors that make the diagnosis of AD unlikely include sudden onset and focal neurological findings such as hemiparesis and visual field deficits. Clinically, both the NINCDS-ADRDA criteria and the Diagnostic and Statistical Manual of Mental Disorders IIIR definition of Dementia of the Alzheimer Type (DAT) may be used to diagnose AD with 90% accuracy. 8
The differential diagnosis for AD is extensive and includes a multitude of neurodegenerative diseases that are associated with the development of dementia including Pick's disease, Lewy body disease, and progressive supranuclear palsy as well as other diseases such as vascular dementia and Creuztfeldt-Jakob Disease. Most of these entities can be differentiated from AD by the clinical history and a careful examination. Potentially treatable diseases that may mimic the dementia caused by AD include depression, thyroid disease, vitamin B12 deficiency, normal pressure hydrocephalus and neurosyphilis all of which should be effectively ruled out in the evaluation of AD.
In advanced cases of AD, computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate diffuse cortical atrophy with disproportionate volume loss in the medial temporal lobe structures. However, only mild atrophy and normal age-related changes may be present early on in the disease. Therefore, the utilization of imaging studies in the diagnostic workup of AD is mainly to exclude structural lesions such as subdural hemorrhage and brain tumors. 9 Functional imaging studies used in clinical research include positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans which demonstrate hypometabolism and hypoperfusion respectively in the temporal-parietal regions bilaterally.
Routine chemistry panels, blood counts, spinal fluid analyses and inflammatory markers are all within normal limits in patients with AD. Elecroencephalographic (EEG) recordings are usually normal or show diffuse slowing in later stages of the disease.
The drugs that are available for the treatment of Alzheimer's disease can be divided into those whose actions enhance the effect of neurotransmitters and those thought to protect neurons. The former category represents the palliative approach, the latter the restorative approach.
Alzheimer's disease is associated with a decrease in acetylcholine levels, and it seems reasonable that replacement of this neurotransmitter might alleviate some of the clinical effects of the disease. One way to achieve higher levels of acetylcholine is to prevent its breakdown by acetylcholinesterase, also known as cholinesterase. This is what the cholinesterase inhibitors tacrine and donepezil do. A centrally acting cholinesterase inhibitor, tacrine is labeled for the treatment of mild to moderate Alzheimer's disease. Donepezil. Act in same way as tacrine.
Donepezil is not associated with the hepatotoxicity that occurs with tacrine. The initial dosage is 5 mg once daily; this may be increased to 10 mg per day after six weeks.The use of tacrine and donepezil is associated with cholinergic side effects, particularly nausea and vomiting. These effects may subside with continuing therapy. In addition, the beneficial effects of both drugs cease within weeks of discontinuation. 10 Patients and their families should be informed that these drugs, although the best available and the only drugs labeled for this use at present, are only modestly effective and may be associated with intolerable side effects. In fact, clinical studies reveal that caregivers usually note no improvement. Rivastigmine and metrifonate are under same class.
Hydergine is the trade name for a mixture of ergoloid mesylates that differs from other ergot alkaloids in having no vasoconstrictive effects. This agent enhances the sensitivity of neural receptors. It has been labeled by the FDA for use in treating the symptoms of an idiopathic decline in mental capacity not related to a potentially reversible condition. Some studies show a statistically significant improvement in alertness and recent memory, and a decline in confusion, but others show no benefit. A meta-analysis of Hydergine's efficacy, published in 1994, showed statistically nonsignificant improvement in some psychologic and behavioral measures in patients with Alzheimer's disease. Patients with vascular dementia were more likely than others to experience benefit from this product. A related compound, nicergoline, has been shown to be effective in improving cognition in vascular dementia and is currently in use in Europe.
Investigational Neurotransmission-Enhancing Drugs Nicotine
This drug has been proposed as a treatment for Alzheimer's disease because patients with this disease have fewer nicotinic cholinergic binding sites than control subjects, and nicotine is known to stimulate acetylcholine receptors. The results of a small pilot study suggest that nicotine can improve cognition in some patients with Alzheimer's disease. Phase 3 trials presently under way may establish a role for nicotine in treating this disorder, but its use cannot be recommended at the present time.
Administration of a dried extract of leaves of the Ginkgo biloba tree has recently been approved in Germany for treatment of dementia.Ginkgo may also have antioxidant properties. In a recent American trial, ginkgo-treated patients showed no worsening of their cognitive impairment, as measured by the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS), while a 1.5-point decline was demonstrated in the placebo-treated group.
Other Investigational Drugs
It is hypothesized that glutamate and aspartate accumulate at N-methyl-D-aspartate (NMDA) receptors in the brains of patients with Alzheimer's disease, causing hyperdepolarization and, possibly, degeneration of neurons. Drugs that can regulate or enhance the function of these NMDA receptors may have a positive effect on the disease. CX516 is a drug that has been shown in small trials to significantly improve learning and memory when compared with placebo. It did not improve all aspects of memory, but further research may prove that even selective improvement is useful in patients with Alzheimer's disease.
Stimulation of nerve growth with neurotrophic factors is also being considered as a treatment for degenerative disorders such as Alzheimer's disease.
Investigational Neuroprotective Agents
No drugs thought to be restorative have been labeled by the FDA for use in treating the cognitive symptoms of patients with Alzheimer's disease. However, researchers are hopeful that some commonly used agents, such as estrogen, vitamin E and nonsteroidal anti-inflammatory drugs, may prove to be useful in the treatment of this disease
The facts that the risk of developing Alzheimer's disease increases dramatically after age 65 and that women seem to be more susceptible (independent of their longer life spans) has led researchers to investigate the possible cognitive effects of sex hormones, which decline in women after menopause (testosterone does not normally decline sharply in men). Animal studies have shown that administration of estrogen to estrogen-deficient laboratory animals restores the number of neural synapses, causes beta-amyloid to be more soluble and has an antioxidant effect. A recent descriptive study in which participants were asked to self-report their use of estrogen showed a lower relative risk (0.40) of Alzheimer's disease and a later onset of dementia in those who had taken estrogen, compared with those who had not. The optimal dosage to achieve these effects is uncertain. The apparent benefit was increased if the length of treatment was more than one year.
Prospective studies are lacking, and the evidence at this time is not sufficient to recommend administering estrogen to prevent or delay progression of Alzheimer's dementia. However, the preliminary (and somewhat promising) evidence of estrogen's effect on cognition should be reviewed with women who are considering the risks and benefits of estrogen replacement therapy.
Vitamin E and Selegilin
Substances that increase brain catecholamines and/or reduce oxidative damage to neurons may slow progression of Alzheimer's disease. Vitamin E has an antioxidant effect. Selegiline is a selective monoamine oxidase B (MAO-B) inhibitor that might be effective since MAO-B stimulates oxidation in the brain.
Patients taking vitamin E or selegiline fared better than those taking placebo or the two drugs together. The delay in functional decline was equal to approximately a seven-month delay in one of the above-mentioned outcomes. Cognitive function was not affected in any of the groups. Patients taking selegiline alone or in combination with vitamin E did have a non-significantly higher rate of falls than those taking placebo, although there were no serious injuries.
Vitamin E is considered to be safe and nontoxic, although patients may complain of nausea, intestinal cramping, fatigue or blurred vision. Gonadal dysfunction and abnormalities in serum creatine kinase, thyroid or lipid test values may also occur rarely. Vitamin E, especially in higher dosages, may also increase the risk of coagulation defects in patients with vitamin K deficiency and in those taking warfarin.
Selegiline is associated with orthostatic hypotension. In addition, it should not be given to a patient taking selective serotonin reuptake inhibitors, tricyclic antidepressants or meperidine, or receiving general anesthesia, because of a risk of severe central nervous system toxicity. A tyramine-free diet is not required, since selegiline is a selective MAO-B inhibitor at the dosages considered here (no more than 10 mg per day). Patients should be warned about the possibility of hypertensive crisis with selegiline therapy and the symptoms to watch for, especially if the standard 10 mg per day dosage is exceeded. Selegiline is not labeled by the FDA for treatment of Alzheimer's disease.
Nonsteroidal Anti-inflammatory Drugs. ,
Investigators noted in the 1980s that patients with rheumatoid arthritis had a lower incidence of dementia than would be expected in the general population. It was hypothesized that nonsteroidal anti-inflammatory drugs (NSAIDs) decreased inflammatory changes in the brains of patients with Alzheimer's disease. Participants in a recently reported long-term observational study on aging were asked to self-report their use of over-the-counter medications.The risk of developing Alzheimer's disease was found to be about 50 percent less in those who were using NSAIDs. (The most commonly used NSAID was ibuprofen; most people reporting aspirin use were taking dosages too low for an anti-inflammatory effect.) The optimal dosage for these medications is not known, but participants in the study had taken NSAIDs for more than two years.
NSAIDs are associated with gastrointestinal and renal complications. They cannot be recommended for the treatment of Alzheimer's disease at present, but patients who need NSAIDs for other indications should consider the early evidence of possible benefit in preventing Alzheimer's disease when deciding whether or not to take these medications
Anand Pithadia 93, Swaminarayan Nagar, Nizampura, Vadodara, Gujarat, India- 390 002 Ph No. +91-9825240367 e.mail: anand_subtle@ yahoo.com