Alzheimer’s disease
INTRODUCTION
The management of patients with AD is one of the urgent problems of modern medicine, because AD is one of the most common causes of acquired cognitive impairment (CI) and, as a result, disability among the elderly [1]. Currently, more than 44 million people suffer from dementia, and 5 to 7 million new cases of dementia are registered every year [2, 3]. The number of patients with dementia may double by 2030 and triple by 2050; therefore, prevention of the development and progression of CR is regarded as a priority public health problem [3].
Currently, the problem of CI is of particular relevance due to the possibility of diagnosing AD at an early stage, when there are no pronounced CIs, or even with normal cognitive functions in people with biological markers of AD and (or) a confirmed hereditary mutation. Statistical calculations show that if any method of prevention slows down the development of dementia for one year, its frequency will decrease by 7-10%, if it slows down for 5 years – by 40-50% [4].
AD is the most common degenerative brain disease that leads to the development of cognitive impairment, it occurs mainly in the elderly and senile age, over the age of 60 years, asthma occurs in almost 5% of people, over the age of 85 years – in 30-40%; women get sick more often than men [5]. AD is currently considered as a genetically determined disease with a significant influence of environmental factors on the rate of implementation of the innate genetic program; family cases of this disease are relatively rare (less than 10% of cases ) and are characterized by an early onset (fifth or sixth decade of life) and rapid progression; Most cases of AD with onset in old age are sporadic, they are associated with carriage of the 4th allele of the apolipoprotein E gene [5].
Currently, there is no convincing evidence of the effectiveness of any drug or non-drug method for the treatment and prevention of asthma, however, some drugs and non-drug methods have a basis for use in everyday practice.
Psychosocial and behavioral guidelines form the basis of the management of the patient with AD, they should be used as early as possible and remain throughout the rest of life. Ideally, family members, caregivers and attending physicians (family doctors, neurologists, psychiatrists), psychologists form a single team providing various non-drug treatments [6, 7]. Family members and caregivers inform doctors about changes in the patient’s condition, the effectiveness of various therapies. It is recommended to keep the patient as active as possible in family affairs, for example, in cooking, caring for the garden and garden, to facilitate, if possible, his communication with friends, acquaintances and neighbors. Various aspects of the patient’s behavior are discussed with doctors, and it is recommended to encourage any physical and mental activity of the patient, to avoid conflict situations, such as meetings with neighbors or acquaintances, which may end in a conflict situation, a scandal. With the appearance of aggressiveness, dangerous behavior for others, a psychiatrist’s consultation is required.
Delicate information is needed for the patient, his family members about the nature of asthma, its course, symptoms and prognosis. It is necessary to find out the patient’s opinion regarding further care with the progression of the symptoms of the disease, discuss with him and his relatives the solution of financial, legal and other issues. It is advisable to find out the patient’s attitude to possible medical methods of treatment in case of emergency situations caused by a deterioration in the condition: artificial lung ventilation, parenteral feeding, treatment of emerging concomitant infectious diseases. When diagnosing asthma, as well as during periods of its progression, psychological and psychotherapeutic assistance is indicated not only for the patient, but also for his family members.
More than 44 million people currently suffer from dementia, and between 5 and 7 million new cases of dementia are reported each year. The number of patients with dementia may double by 2030 and triple by 2050, so preventing the development and progression of CI is regarded as a priority public health problem
Cognitive training is of great importance for the preservation and maintenance of cognitive functions in patients with AD. Cognitive training provided by trained professionals is usually well received by the patient and his family members, can be accompanied by a significant improvement in cognitive performance, has a beneficial psychological effect and does not have undesirable consequences. Training showed good results in moderate cognitive impairment, as well as in patients at risk of AD [8]. Cognitive stimulation should be directed to various cognitive functions, which is more effective than training one of the functions [9]. Frequent and short sessions are more effective than infrequent and long ones [10]. It is possible to influence the patient’s lost or reduced functions through less impaired or preserved functions, for example, memorizing words with the help of visual images in case of auditory -speech memory impairment, work with fine motor skills of the hands to improve the processes of memorization and speech.
Psychosocial and behavioral guidelines form the basis of the management of the patient with AD, they should be used as early as possible and remain throughout the rest of the life.
It is advisable to combine cognitive training with musical breaks in which patients can dance or just listen to music, color effects, and aromatherapy. These methods are used primarily to reduce sensory deprivation that occurs in a patient with visual and hearing loss, as well as with a lack of communication. Influence on different sense organs can contribute to better memorization of information and improve memory.
TREATMENT OF PSYCHOTIC DISORDERS AND DEPRESSION
With the development of severe psychotic disorders, various antipsychotics can be used, but their use is associated with a deterioration in the cognitive functions of patients, an increased risk of death, and the development of extrapyramidal complications, including neuroleptic malignant syndrome [18]. Long-term follow-up of patients suffering from asthma and taking antipsychotics shows that they die faster than other patients [19, 20]. Prescribing antipsychotics is most dangerous for patients with asthma suffering from cardiovascular and pulmonary diseases. Therefore, the use of antipsychotics is recommended only in patients with a low risk of complications and (or) in cases where there is no effect from other therapies [18, 21].
With the development of depression in patients with AD, the clinical picture of which is usually dominated by anhedonia, anorexia, weight loss and insomnia , the leading place is given to psychotherapeutic methods of influence. It is recommended to increase communication with friends, acquaintances, to promote an increase in doing what you love, to avoid stressful and unpleasant situations, to undergo a course of psychotherapeutic treatment. Antidepressants may be effective, among which selective serotonin reuptake inhibitors are preferred; the use of tricyclic antidepressants is associated with the risk of deterioration of cognitive functions due to their anticholinergic action. However, the results of randomized placebo-controlled trials do not show a significant improvement in the condition of patients with dementia when using antidepressants, such as sertraline [22].
NON-DRUG METHODS OF PREVENTION AND TREATMENT
Regular physical activity , which forms the basis of a healthy lifestyle, can prevent the development of dementia by reducing body weight, lowering blood pressure (BP), increasing tissue glucose tolerance, increasing blood supply to the brain, and a number of other possible changes. Regular physical activity reduces the risk of developing various cardiovascular diseases, including stroke, the occurrence of which often provokes and enhances the development of the degenerative process underlying AD.
Regular physical activity reduces the risk of developing various cardiovascular diseases, including stroke, the occurrence of which often provokes and exacerbates the development of the degenerative process underlying AD
Long-term follow-up of older people shows that regular physical activity is combined with a slowdown in the progression of cognitive disorders and a decrease in the incidence of dementia [23]. A follow-up of 1,740 people aged 65 years and older for 6 years showed that regular physical activity is associated with a decrease in the incidence of dementia [24]. A follow-up of 2,736 elderly women without signs of dementia (at baseline) found that cognitive function remained better, and cognitive impairment occurred less frequently if the women were highly physically active [25]. A meta-analysis of prospective studies has shown that the risk of developing AD in people over 65 is lower if they are physically active throughout their lives [26].
The duration, intensity and nature of physical activity remain unclear, in many respects they require an individual approach, taking into account existing experience and concomitant diseases. In general, older people with and without cognitive impairment are shown walking for at least 30 minutes three times a week and (or) aerobic exercise or sports [23].
Proper nutrition plays an important role in the prevention of many age-related diseases. Antioxidants contained in fresh fruits and vegetables can reduce the processes of oxidative stress, which is of great importance in the development of AD [27]. To some extent, this is associated with a decrease in the incidence of stroke, cardiovascular disease, which are risk factors for cognitive impairment, as well as with a decrease in inflammation and metabolic disorders in the brain.
A follow-up of 3,700 elderly people over 6 years showed that high vegetable consumption was associated with a reduced risk of developing cognitive impairment [28]. However, in patients with AD, an antioxidant-rich diet does not provide a significant positive result [27]. It is possible that antioxidants, which weaken the processes of oxidative stress, have a positive effect mainly in healthy people (without cognitive impairment) and do not have a significant effect in the case of the death of a large number of neurons that occurs in AD.
Mediterranean diet, which includes the use of a large amount of antioxidants (fresh fruits and vegetables ), polyunsaturated fatty acids (fish and other seafood), is associated with a decrease in the incidence of AD, mild cognitive impairment, and the rate of their progression to dementia [29]. Moderate wine consumption (250–500 ml per day) has been shown to be associated with a reduced risk of dementia compared with greater alcohol consumption or avoidance [30].
Long-term education and regular mental work create a cerebral reserve that makes it possible to slow down the clinical manifestations of organic brain damage caused by AD [1] . Functional methods of brain research demonstrate that people who have received a high level of education and are engaged in mental work for a long time have less significant cognitive impairment in the presence of degenerative brain damage than people with a low level of education and mental activity [31]. Therefore, there is every reason to recommend mental activity to both healthy people and patients with cognitive disorders. Specific recommendations should take into account individual characteristics , acquired interests and the level of education of the patient.
STROKE PREVENTION
Stroke prevention is of great importance both in the prevention of AD and in the prevention of the progression of cognitive impairment in patients with AD. Stroke prevention includes both non-drug methods (cessation of smoking and alcohol abuse, weight loss, sufficient physical activity, proper nutrition) and drugs (antihypertensive agents, antithrombotic agents, statins ) [ 32 ] .
Normalization of blood pressure based on antihypertensive therapy is one of the possible ways to prevent dementia and milder cognitive impairment in patients with arterial hypertension. Of particular importance in this aspect is antihypertensive therapy in elderly patients with a high risk of developing dementia in the coming years. The Canadian Medical Association recommends a gradual decrease in systolic blood pressure to 140 mm Hg for people over 60 years of age . Art. to reduce the risk of dementia, which is regarded as a high (I) level of evidence recommendation for the population [33]. The appearance of even mild cognitive impairment in patients with arterial hypertension requires more active measures to control blood pressure and, apparently, more aggressive antihypertensive therapy, although it is necessary to avoid a rapid and significant decrease in blood pressure, which can lead to a decrease in cerebral blood flow and worsening cognitive functions.
DRUG-BASED PREVENTION OF AD
The use of non-steroidal anti-inflammatory drugs (NSAIDs), according to several meta-analyses, is associated with a decrease in the incidence of dementia [34, 35]. However, multicenter placebo- controlled studies have not shown the effectiveness of NSAIDs (with a significant increase in the number of undesirable, mainly gastrointestinal complications), in particular naproxen (220 mg three times a day) or celicoxib ( 200 mg twice a day) [ 36]. At present, there is no evidence to recommend NSAIDs for the prevention of dementia, however, if a patient is forced to take NSAIDs constantly due to the disease, it is likely that he has a reduced risk of developing AD.
Functional methods of brain research demonstrate that people who have received a high level of education and are engaged in mental work for a long time have less significant cognitive impairment in the presence of degenerative brain damage than people with a low level of education and mental activity.
Estrogen replacement therapy in women, according to a meta-analysis of several studies, is associated with a reduction in the risk of developing dementia by almost one-third [37]. However, a large study that included 75,000 women, on the contrary, showed that estrogen replacement therapy increases the risk of developing dementia and mild cognitive impairment [38].
The use of vitamins has not been proven as a means of preventing dementia; when using vitamins E and C, no effect was obtained [39]. In most placebo-controlled studies that evaluated the effect of folic acid and B vitamins (B6 and B12) on the development of cognitive impairment in hyperhomocysteinemia , there was no significant reduction in the progression of cognitive impairment; only in one study, against the background of taking folic acid, a slowdown in the progression of cognitive impairment was observed [40]. In general, there is currently no convincing evidence that the correction of hyperhomo – cysteinemia prevents the development of cognitive disorders, however, in all cases of its detection , treatment seems reasonable for the prevention of stroke.
Preparations of a standardized extract of ginkgo biloba – EGb 761 were studied as a means of preventing dementia in 2 large placebo-controlled randomized trials [ 41, 42]. In the USA, 2,851 people with normal cognitive functions and 481 patients with moderate cognitive impairment were included in the study , who began to take EGb 761 at 120 mg twice a day or placebo, there was no significant advantage of EGb 761 over placebo [41 ]. A large, multicentre, placebo-controlled trial was completed in France investigating the efficacy of a standardized extract of EGb 761 (tanakan ) in the prevention of dementia in 2,854 patients aged 70 years or older (mean age 78 years) with a complaint of memory impairment; there was no significant benefit of EGb 761 over placebo [42]. A recent meta-analysis noted the effectiveness of EGb 761 for the treatment of behavioral disorders in patients with AD [ 43].
FEATURES OF MANAGEMENT OF THE PATIENT IN OUR COUNTRY, THE USE OF CEREBROLYSIN
In our country, AD is poorly diagnosed; patients are often observed with an erroneous diagnosis of chronic vascular lesions of the brain, even in cases of classical manifestations of the disease [44]. According to our data, at least 10% of elderly patients who are seen in a polyclinic with a diagnosis of chronic cerebrovascular disease suffer from BA [44, 45]. Such patients are observed for a long time (several years) in a polyclinic with a diagnosis of dyscirculatory encephalopathy (or chronic cerebral ischemia), they do not have an assessment of their cognitive functions , they (and their relatives) do not receive effective psychological and behavioral methods that counteract – mental drugs, they undergo course treatment with drugs in order to improve the blood supply to the brain .
In our country, among not only patients, but also doctors , the priority in the treatment of patients with various brain diseases is parenteral (injection) prescription of drugs. Among all drugs registered in our country , only cerebrolysin has been studied in detail in the treatment of AD.
Cerebrolysin is a natural product derived from porcine brain and contains biologically active polypeptides and amino acids that have multimodal beneficial effects on the brain. The experiment showed that the active substances of cerebrolysin have an effect on brain neurons similar to the effect of nerve growth factor [46]. An increase in neuronal plasticity and the number of dendrites, the formation of new synapses, activation intraneuronal metabolism, activation of neurogenesis , formation of new vessels and improvement of blood supply to the brain.
Cerebrolysin is a natural product derived from porcine brain and contains biologically active polypeptides and amino acids that have multimodal beneficial effects on the brain.
Cerebrolysin is effective in improving cognitive function in AD according to a 2007 meta-analysis that included 772 patients who received Cerebrolysin at a dose of 10 to 60 ml per day for at least a month [47]. Cerebrolysin at a dose of 30 ml 5 days a week for 4 weeks reduces the severity of clinical manifestations of AD , the effect persists for 6 months, and the number of patients who do not respond to treatment with acetylcholinesterase inhibitors decreases [48]. The results of placebo-controlled randomized trials conducted in Canada, Southeast Asia, Austria and Russia indicate that intravenous administration of cerebrolysin 10-60 ml/ day has a beneficial effect on cognitive functions and daily functioning in patients with AD, mild or moderate vascular dementia [ 48, 49]. The advantageous aspects of the use of Cerebrolysin include its effectiveness in CI of various etiologies ( neurodegenerative , vascular ), good tolerability , possible neuroprotective and neurotrophic effect (activation of reparative processes in the brain). The effect of a course of treatment (20 infusions) can be maintained for up to 6 months. One of the latest meta-analyses in 2015 included 6 placebo-controlled trials of cerebrolysin (duration ≥4 weeks ) in mild to moderate AD [49]. Efficacy ( in terms of cognitive functions and overall clinical impression) and safety of using Cerebrolysin 30 ml IV 5 days / week for 4 weeks were noted. The meta-analysis calculated the number of patients who need to be treated to get one positive effect of therapy (3 patients), and the number of patients in whom treatment is complicated by one adverse event requiring discontinuation of therapy (501 patients), which reflects favorable benefit/risk ratio when using cerebrolysin [49].
VACCINATION METHODS
Currently, methods of pathogenic genetic therapy aimed at reducing the formation of beta-amyloid and tau protein with the help of special vaccines and sera are being actively studied. The accumulation of beta-amyloid in the extracellular space of the brain, which has a toxic effect on neurons, is considered as an important cause of dysfunction and death of neurons in AD; therefore, in the last 20 years, methods have been studied aimed at preventing the formation and accumulation of beta in the brain. – amyloid [ 50] . However, these treatments did not give a positive result, immunization was accompanied by serious side effects; they continue to be actively studied, but are not widely used in clinical practice. It is assumed that vaccination is most effective in the early stages of the disease. However, the first studies using drugs monoclonal antibodies in patients in the early stages of AD did not have a clinically significant effect. Currently, the drug Adukanumab is being tested , which, unlike other antibodies , binds not only to amyloid oligomers, but also to insoluble beta-amyloid fibrils [51]. The drug has already shown a dose-dependent effect in phase 1b trials in patients with preclinical AD and mild cognitive impairment in terms of reducing amyloid accumulation and slowing cognitive decline .
Thus, in the management of patients with AD, psychosocial and behavioral methods play a leading role.
Stroke prevention based on normalization of blood pressure and, if necessary, taking antithrombotic drugs and statins , can reduce the risk of developing asthma and the progression of its symptoms.
The use of antidementia drugs (AChE inhibitors, Akatinol Memantine ) is able to improve cognitive functions . In our country, AD is poorly diagnosed , most patients are diagnosed with chronic cerebral ischemia ( dyscirculatory encephalopathy), and Cerebrolysin is the most justified use as a popular injectable drug . For the prevention of asthma, it is advisable to use non- drugs : consumption of large amounts of fresh fruits or vegetables, a Mediterranean diet, regular exercise and mental activity. Stroke prevention , based on normalization of blood pressure and, if necessary, on the use of antithrombotic drugs and statins , can reduce the risk of developing AD and the progression of its symptoms.