ALZHEIMERS DISEASE. MODERN DRUG TREATMENT

     Alzheimer's disease (AD) - a degenerative brain disease, manifested by a progressive decline in mentality. And, over time a person loses the ability to take care of themselves. First described by German physician A. Alzheimer in 1907 and as at the present time, it has become clear, is one of the most common form of dementia. Only in the U.S. AD, according to the 2007 statistics, affects about 5 million people, and by 2050 their number, according to some forecasts, will reach 13 million. In U.S. nursing homes account for 30% of the quota is a person with AD. Although the disease often remains unknown, the reason why it would be somewhat lower, it is the fourth leading cause of death. In the USA from it, are estimated to die more than 100 thousand people per year [1, 2].

     Since the first time AD has been described in patients younger than 65 years, it previously was called "presenile dementia." And mistakenly viewed as "a manifestation of aging," or "sclerosis of cerebral vessels." In fact, it is now clearly established, the disease is associated with degeneration of nerve cells (neurons). AD roughly equally affects all nationalities and is practically independent of socio-economic status of the individual. The earliest onset of the disease recorded in 28 years old, but usually it occurs after 40-50 years. In this regard, AD decided to divide into two types - Type I with the manifestation of the disease after 65 years of age, and Type II, when the disease manifests itself earlier. It is noted that the number of cases doubles every 5-10 years of age. For groups 65-69, 70-74, 75-79, 80-84 and over 85 years, the frequency of AD, respectively, 0.6%, 1.0%, 2.0%, 3.3% and 8.4% [3, 4].

     Risk factors, other than age, for the development of AD are family history of the disease, carried in the past traumatic brain injury (TBI), disuse of nonsteroidal anti-inflammatory drugs (NSAD), certain genetic factors, as well as female gender, low educational level of the individual, concomitant disease and certain features of the environment. Some of them are worth investigating more:

     The level of education. Effect of mental stress on the aging process in general and dementia, in particular, has long interested researchers. Except for the purely philosophical ideas that have very long-standing origins, it should be noted that the sighting epidemiological studies of this issue have been held only in the last 20 years. The results clearly point to either a neutral or prophylactic effect of education (skilled learning) for the development and course of dementia. That is, increased risk of dementia for people with low educational level. The researchers argue that any systematic training increases the "cognitive reserve" a person who, in turn, provides a longer period of AD before the appearance of clinical signs. The disadvantage of these studies is the polyvalence, which is not possible to formulate specific medical advice. For the concept of "education" can mean lower demand for their diet, behavioral stereotypes, higher frequency of alcoholism, smoking, etc. At the same time, the focus of the study is currently limited to a small volume of existing neurochemical knowledge that, for example, now do not allow us to quantify the nature of certain mental activities (reading, memorization, games, etc.) [5, 6].

     Traumatic brain injury. The contribution of TBI in all forms of dementia is generally not less than 15%. Chronic repetitive head trauma (eg, boxing), even with the 20-s of last century are described in the form of Dementia pugilistica, which is largely similar to the clinical and histological features of AD. Moreover, its course is usually complicated by vascular complications and secondary parkinsonism. At the present time as a separate nosological entity of its existence is disputed [7, 8].

     NSAID. While noting the lower incidence of AD among patients with rheumatoid arthritis who constantly and in large doses, take anti-inflammatory drugs, mainly NSAIDs. There is also evidence that NSAIDs improve the results of neuropsychological tests in patients with AD (eg, according to the test MMSE (Mini-Mental Status Examination). This may also indicate that inflammation may play a role in the etiopathogenesis of asthma [9 , 10].

     The main symptoms of AD are very diverse, but generally boil down to a gradual decline of memory and attention. Types of disease (after 65 years old and younger), although having some differences of clinical course, but the basis is a violation of both the processes of thinking and learning ability. It is noted characteristic disorientation in time and area, difficulty finding suitable words, difficulty in communication, changes in the properties and structure of the individual up to the complete loss of ability to self-service. All this can be combined with neurological symptoms (epileptiform seizures, convulsions, etc.). This process can take several years, bringing suffering to the patient and his family.

     Etiopathogenesis. The cause of Alzheimer's disease is currently unknown. Although now a wealth of factual material. The persistence of numerous studies aimed at clarifying the role in the pathogenesis of AD viral infection, heredity, pathological immune responses, environmental factors and a variety toxic substances. The purpose of this research - to optimize the prevention and treatment of AD, because they considered effective at the present time it is not possible.

     In particular, the genetic predisposition to AD in the present - it is clearly established fact. Without touching the detailed features of the inherited chromosomal aberrations and the production of specific proteins, we note that they include several genetically heterogeneous forms, united by similar clinical and histopathological features. In particular, this gene amyloid precursor protein (APP) on chromosome 21, the gene apolipoprotein E (ApoE) on chromosome 19, gene presenilin-1 on chromosome 14 and gene presenilin-2 on chromosome 1 [2, 10].

     While the results obtained from this area do not go into medical practice. The pathology of APP is characterized by early onset AD (under age 65) and monogenic autosomal dominant nature of inheritance. But these changes can be explained only 3-5% of all pedigrees with early-onset disease. It is important that such changes are not detected in patients with late-onset AD (more 65 years old). Similarly, in the ApoE polymorphism does not correlate with the severity, course and prevalence of the disease, which can be regarded only as a risk factor for dementia. At the same time, a relatively recent discovery of preseniline genes responsible for most cases of early familial forms of the disease, gives us some hope. According to preliminary estimates, they may be responsible for 60-70% of the mentioned forms of AD [11, 12].

     Diagnosis. The specific diagnosis of AD is currently unavailable. In this regard, the doctor must first rule out other diseases that cause symptoms of dementia (tumours, trauma, infection, various metabolic disorders, overdose of drugs, mental disorders). AD can only confirm the microscopic examination of brain tissue, which is usually done posthumously. Only occasionally is carried out in vivo on the basis of biopsies of brain tissue. The difficulties caused by the need to differentiate between different types of dementia: vascular, dementia-type Levy (with Lewy bodies), against Parkinson's disease, fronto-temporal, mixed, etc. At the same time, as noted above, AD is the most common cause of dementia in the elderly - it occurs in 50-60% of patients (most new research indicates over 70%) and a further 15-20% is a combination of AD and vascular dementia [ 10, 13].

     Microscopy of the brain in patients with AD found neurofibrillary tangles and neuritic plaques.  Tangles are diseased neurons with abnormal proteins and plaques - deposits are regions in the intercellular space of protein-carbohydrate complexes - amyloid. It is noted that the more brain plaques and tangles, the more pronounced intellectual disturbances. The data of this study quantitatively evaluated according to criteria of CERAD (Consortium to Establish a Registry for Alzheimer's Disease.

     At present, diagnosis of AD is the basis of clinical evaluation. It requires a detailed understanding of complaints not only from the patient, but also his relatives. Often, to identify specific symptoms and behavioural disturbances of memory are required for long conversations with the patient's physician. An example of a screening test and analysis of speech, mental status is presented in table 1.

Table 1.

Evaluation of cognitive functions in patients with Alzheimer's disease

     Treatment. Because of the ambiguity of the pathogenesis, AD initial treatment is mainly symptomatic. And in essence it is aimed at treating the consequences of the disease - dementia. Therapy slows the progression of the symptoms temporarily, but complete healing is not currently possible. In this regard, plays an important role as a device to the patient and the people around them to illness, i.e. non-drug therapies. In this respect, the patient is strongly recommended that as much as possible to an active lifestyle. If you have any delusions, agitation, hallucinations, or other changes in the behaviour of the corresponding assigned additional symptomatic medication (antidepressants, anxiolytics, antipsychotics). However, all these groups of drugs are not relevant to the specific treatment of the disease and are not recommended FDA for Alzheimer's disease.

In general, the currently used drugs can be divided into pathogenetically substantiated and potentially applicable. The first consists of cholinesterase inhibitors II generation and memantadin  (Table 1), and the second - a few others.

     Cholinesterase inhibitors. At the present time are the basis of therapy and presented with four second-generation drugs (selective reversible) cholinesterase inhibitors (ChE), which are approved by the FDA. The mechanism of action related to the blocking effects of ChE in the CNS. Designed for soft and medium-severity forms and stages of AD and can slow down the degradation of the cognitive functions of the patient for 3-6 months per year. In the past, has been widely used drug is the first generation (non-selective reversible inhibitors of ChE) - tacrine. He is still on sale, but due to side effects and low efficiency is not currently recommended and not supported by even its manufacturer. This group is a commercially available ipidacrine (neuromedins, amiridin) (Table 2).

     The reason for using ChE inhibitors directed at relief of symptoms of AD, i.e., palliative treatment is carried out to mitigate the symptoms of the disease. It also helps to slow the progression of deterioration cognitive violations. At the same time anticholinesterase effect is accompanied by a number of dose-dependent side effects. Most common among them: 1) Violations of cardiac function: increased heart rate, bradycardia, 2) Disorders of the nervous system: dizziness, headache, drowsiness, weakness, seizures, 3) Disorders of the respiratory system: increased bronchial mucus secretion, bronchospasm, 4) Violations of the gastrointestinal tract function: increased salivation, nausea, vomiting, diarrhea, jaundice, chest pain, 5) Changes in skin and subcutaneous tissue: sweating, skin rashes and itching, 6) Violations of the reproductive system: increased uterine tone. In the second generation ChE inhibitors are much less pronounced, but in many cases can cause withdrawal [14, 15].

     Memantine is currently the only drug that is FDA approved for the treatment of late-stage symptoms of AD. The mechanism of action of its radically different from ChE inhibitors. The drug protects nerve cells from the brain of excess glutamate, which is formed in the damaged glia cells. That, in turn, leads to the degeneration of astrocytes. The drug blocks this process, adjusting the exchange intracellular glutamate. For over 10 years used in Europe and in U.S. - from October 2003. Side effects include dizziness, anxiety, fatigue, irritability, cold symptoms, increase in blood pressure. Also available are constipation, diarrhea, and weight gain.

     It should be noted that the available clinical data on the use of memantine in practice is mixed. One randomized clinical trial of 252 patients with AD showed a significant reduction in some symptoms of AD at a very low incidence of side effects. The second, involving 350 patients, found no statistically significant benefit for 24 weeks of treatment. A Cochrane systematic review reported for moderate to severe AD, only small positive changes of cognitive functions and behaviour after 6 months of therapy. The latter is confirmed in three other studies, where the positive was hardly definable clinically. It is believed that the effect of memantine on the influence of nonspecific mediated mechanisms of vascular dementia, i.e. nonspecific with regard to AD. This indirectly indicates a more significant results for other neurodegenerative diseases caused by this mechanism is the development (Huntington's disease, AIDS-dementia and vascular dementia) [16, 17].

In Fig. 1 is a specific treatment algorithm for use in AD according to the recommendations of the National Institute on Aging [3, 4].

Fig. 1. The tactics of particular drug treatment of Alzheimer's disease.

     Potentially applicable to the type of treatment may include the use of some other drugs.

     Ginkgo biloba. At the present time was studied in three representative studies in 563 patients with mixed dementia of mild to moderate degree, which was used in doses of 120 and 240 mg/day. Duration of treatment was 3-12 months. Has been shown to significantly influence the drug on general cognitive function of patients, but data on effects of other clinical indicators and for AD were mixed. With increasing doses of growing positive changes neuropsychological tests, clinical scores improved behaviour/mood for the six-month term of its use. None of the studies have not studied the dynamics of changes in load on caregivers. The level of the side effects of treatment was equal to 3 points, and in one study was 6%. Among them were the main symptoms of allergic skin, gastrointestinal dysfunction and headache. Some of them are significantly different from control (compared with placebo) [18, 19].

     Cerebrolysin. In the six studies conducted with cerebrolysin in 819 patients with mild to moderate AD severity in a dose of 30 ml/day, 5 days per week for 4-24 weeks, the drug showed a statistically significant improvement in cognitive function. But the results of the drug to specific cognitive functions, according to those studies that examined these indicators have been inconsistent. In the five studies showed a significant positive effect of the drug on the general clinical condition of patients, and in two out of three showed a positive effect on the rate cerebrolysin behaviour/mood. None of the indicator has not been proven to improve the quality of life and reduce stress on caregivers (in this case has not been studied). In two studies, the level of reported side effects totalled five points in two - four points, the rest - 3 and 2 points respectively. Most often noted an increase in body weight, the appearance of severe anxiety and headaches.

     Estrogens. Effects of estrogens replacement therapy was studied in five studies in 247 patients with dementia. In the four of them studied patients with mild to moderate degrees of AD outpatients, and one - were hospitalized with moderate to severe dementia. In one case, use of estrogens in a dose of 0.10 mg/day as a skin patch for 8 weeks. In the other drugs administered at a daily dose of 1.25 mg over 12-52 weeks, or (only for severe degrees of dementia), 2.5 mg for 4 weeks. Wherever found nonsignificant changes in cognitive functions and some of their differing vectors, although the two had a definite positive trend. In all studies did not show significant effect on the general condition, behaviour/mood, quality of life. The level of treatment discontinuation due to adverse events reached for estrogens-replacement therapy 14%. The most frequent vaginal bleeding [20-21].

     Idebenone (Catena, Sovrima, Noben). The most promising drug for AD among nootropics. The influence of the drug was evaluated in four studies on 1153 patients with mixed dementia, mild to moderate severity. In one of idebenone compared with tacrine (the first generation of inhibitors of ChE). The dose varied from 30 to 360 mg/day, and duration of treatment ranged from 90 days to 60 weeks. A positive effect of the drug on general cognitive function and overall clinical assessment of patients, including indicators of behaviour/mood, and quality of life. But the results were statistically comparable. The dynamics of stress on caregivers in any of the studies have not studied [22, 23].

     Nicergoline (Sermion). Mode of action of the drug in the blood supply to the brain caused by the combined effect of α-adrenoceptor blocking (dehydrated ergot alkaloids) and spasmolytic activity (nicotinic acid). Focused assessment of the effectiveness of the drug conducted two studies on 496 patients with AD of mild to moderate severity. Conducted a 6-month course of treatment (30 mg twice daily). As a result, in one study obtained by improving the cognitive function of patients compared to controls, but the second did not produce such data. Moreover, in both of them had a significant number of patients with deterioration of general condition. At the same time in a number of studies in patients with cerebrovascular disorders (without AD) and related memory impairments observed positive effect of nicergoline in the indicated dose. It was significant already after the first month [24].

     Antioxidants. Several targeted studies suggest that oxidative stress is an important pathogenic process associated with aging in general and AD in particular, and the increase of markers of oxidative stress precedes the characteristic pathologic lesions in AD. It is believed (but frankly not enough evidence) that antioxidants may blunt the cognitive impairment and mild degree of disease progression. It has been shown in comparative studies of selegiline and α-tocopherol with placebo. The American Academy of Neurology does not exclude the possibility that vitamin E in combination with vitamin C are associated with a decrease in the prevalence and incidence of AD. However, the findings do not allow us to recommend some interventions [25, 26].

Diet. The importance of certain revenue balance of antioxidants and vitamins is reflected in the views on the necessary diet. Here the prevailing recommendations for the "Mediterranean diet", which already has a bibliography in reducing the incidence of AD. Recent studies have shown that it gives also a decrease in mortality from AD and that this effect is dependent on the extent of compliance. The very same diet characterized by high consumption of vegetables, fruits and cereals, low or moderate levels of saturated fatty acids, and moderately high levels of fish consumption, low to moderate - dairy products, low consumption of meat and poultry, and a moderate amount of alcohol [27].

     Statins. According to some data, the levels of abnormal proteins central nervous system, according to autopsy in patients with AD, decreased under the influence of regular intake of simvastatin. In addition, the study TACTS (The Adult Changes in Thought Study) showed a general protective effect of statins on dementia. Although it was later clarified that he had seen the condition of regular use of these drugs before 80 years. These data confirmed the pre-existing information on the preventive role of statins for the development of AD. Although the last large cohort, placebo-controlled epidemiologic study of the effect of drugs on the development of coronary heart disease showed a protective effect on the inability of cognitive disorder, is the potential for slowing the progression of assumptions about the neurodegenerative processes of the CNS. At the same time, the ability of statins to influence the recovery of existing neuron degeneration is denied [28, 29].

     NSAIDs. The idea of ​​therapeutic use of NSAIDs is based on the mechanism of deposition of specific proteins in brain tissue, which in AD is associated with immune response. The latter, in turn, involves the activation of complement, secretion of proinflammatory cytokines, expression of chemokines, release of nitric oxide, which mediate apoptosis of cellular elements of the CNS. NSAIDs inhibit the inflammatory response of microglial cells and astrocytes directly and may reduce the risk of not only development but also progression of AD. Investigation of BLSA (Baltimore Longitudinal Study of Aging) showed a reduction in the risk of AD in proportion to the duration of NSAID use, particularly in patients with rheumatoid arthritis. They noted and the expected delay in the progression of AD. Accepted that NSAIDs may help prevent cognitive decline when supplementation began in adulthood. However, randomized controlled trials of various NSAIDs failed to show significant effect on the rate of cognitive decline in the already existing dementia, and the impact on the development of specific symptoms in mild cognitive impairment in AD. Moreover, a large randomized controlled trial of primary prevention of AD with NSAIDs was stopped prematurely in 2004 due to a significant increase in the subjects of cardiovascular complications. Given this kind of risk at present and conventional NSAIDs and COX-II inhibitors are not recommended for treatment or prevention of AD [30, 31].

     Neurotrophin. A number of studies with injections of nerve growth factor (NGF and neurotrophins) in the central nervous system of people gave positive results as early as the 1980s. Since 1986, the proven preventive effect of infusion of NGF in the brain of rats with respect to the death of basal forebrain cholinergic neurons in different models (intoxication, trauma, etc.). With the undoubted improvement in the typical cognitive impairment. Similar melon obtained later for the basal parts of the forebrain of monkeys. Nevertheless, the inability of the protein to cross the blood-brain barrier of NGF and its short half-life and a wide range of biological effects in the signal made it impossible to use them effectively in the clinical setting. In addition, the introduction of the mouse NGF in patients with AD, amyotrophic lateral sclerosis and Parkinson's disease have been unsuccessful because of the many side effects. In response to this dilemma have been developed technique administered to the patient NGF-secreting cells, and in 2001 started clinical trials in humans. In phase I of 8 patients with AD received injections of cell suspension in the basal nucleus without complications and side effects. Over the next two years of observation is not detected signs of improper distribution of NGF and 50% of patients received the data conversion to the cortex with a decrease in usual AD metabolic changes. A similar success for the phase I trial was obtained in the way of NGF gene delivery by virus. In the work currently being carried out in respect of a multicenter phase II trials [32, 33].

     Prognosis. Life expectancy in Alzheimer's disease - 8-10 years, with possible variations from one to 25 years. For unknown reasons, in some cases, the disease progresses slowly and continuously, while the other is characterized by long periods of stabilization. Death occurs in most cases of malnutrition, secondary infection or heart disease.

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