Dementia in Alzheimer's disease

Primary degenerative dementia of the Alzheimer's type, or dementia in Alzheimer's disease, is the most common form of primary degenerative dementia of late age with gradual onset in presenile or old age, steady progression of memory disorders, higher cortical functions up to the total disintegration of the intellect and mental activity in general, complex of neuropathological signs.

Examples of the formulation of the diagnosis in view of ICD-10

Alzheimer's disease with late onset (senile dementia of the Alzheimer's type) with other symptoms, mostly delusional; stage of mild dementia.

Alzheimer's disease with early onset (presenile dementia of the Alzheimer's type) without additional symptoms; stage of severe dementia.

Alzheimer's disease of mixed type (with signs of vascular dementia) with other symptoms, mostly depressive; stage of mild (mild) dementia.

[1], [2], [3],

Epidemiology of dementia in Alzheimer's disease

Alzheimer's disease is the most common cause of dementia in the elderly and elderly. According to international studies, the prevalence of Alzheimer's disease after 60 years is doubled every five years, reaching 4% at the age of 75, 16% - in 85 and 32% - in 90 years and older. According to the epidemiological study of mental health in the elderly population carried out in Moscow, Alzheimer's disease affects 4.5% of the population aged 60 and older, with age-related morbidity rates increasing as the age of the examined patients increases (in the 60-69-year-old age group, the prevalence was 0, 6%, at the age of 70-79 years - up to 3,6% and at the age of 80 years and older - 15%). The prevalence of Alzheimer's disease among older women is significantly higher than that of men of the same age.

Alzheimer's disease is the most common cause of dementia in the western hemisphere, accounting for more than 50% of its cases. The prevalence of Alzheimer's disease increases with age. In women, the disease is more common than in men. In the US, more than 4 million patients with Alzheimer's disease. The annual direct or indirect costs associated with the disease reach $ 90 billion.

The prevalence of Alzheimer's disease among persons aged 65.75 and 85 years is 5, 15 and 50%, respectively.

[4], [5], [6], [7], [8], [9], [10], [11],

Causes of dementia in Alzheimer's disease

Genetically determined ("family") forms of Alzheimer's disease account for no more than 10% of cases. Three genes responsible for their development have been identified. Chromosome 21 contains the amyloid precursor gene: chromosome 14-presenilin-1 and chromosome 1-presenilin-2.

Mutations in the amyloid precursor gene are responsible for 3-5% of all presenile family forms of Alzheimer's disease (inheritance occurs in an autosomal dominant type), mutations in the presenilin-1 gene are detected in 60-70% (mutations in this gene are characterized by full penetrance, the disease must manifest itself at the age of 30 to 50 years). Mutations in the gene presenilin-2 are extremely rare and they cause the development of both early and late family forms of the disease (they are characterized by incomplete penetrance).

The role of mutations or polymorphisms of presenilin genes in the development of sporadic cases of late Alzheimer's disease (senile dementia of the Alzheimer's type) remains insufficiently elucidated. The recently identified e4-isomorphic version of the gene for apolipoprotein E is now considered the main genetic risk factor for the development of late Alzheimer's disease.

The numerous neurohistological and neurochemical studies performed so far have allowed the establishment of several cascades of biological events occurring at the cellular level that are presumably involved in the pathogenesis of the disease: a violation of the conversion of beta-amyloid and the phosphorylation of t-protein. Changes in glucose metabolism, excitotoxicity and activation of lipid peroxidation processes. It has been suggested that each of such cascades of pathological events or their combination can ultimately lead to structural changes that underlie the degeneration of neurons and are accompanied by the development of dementia. 

Dementia in Alzheimer's Disease - What Happens?

[12], [13], [14], [15], [16]

Signs of dementia in Alzheimer's disease

In accordance with the diagnostic recommendations developed by international expert groups, and in accordance with the ICD-10 approved by WHO, the intravital diagnosis of Alzheimer's disease is based on the presence of several obligate signs.

Obligatory intravital diagnostic signs of Alzheimer's disease:

• Syndrome of dementia.
• Multiple deficit of cognitive functions is a combination of memory disorders (worsening of remembering new and / or reproducing previously acquired information) and signs of at least one of the following cognitive impairments:
  • aphasia (violation of speech function);
  • apraksii (impaired ability to perform motor activity, despite the preserved motor functions);
  • agnosia (the inability to recognize or identify objects, despite the persistent sense perception);
  • violations of intellectual activity proper (its planning and programming, abstraction, the establishment of cause-effect relationships, etc.). 
• Reduction of social or professional adaptation of the patient in comparison with its previous level due to memory impairment and cognitive functions.
• The subtle start and steady progression of the disease.
• In a clinical study, other CNS diseases (eg, cerebrovascular disease, Parkinson's or Pick's disease, Huntington's chorea, subdural hematoma, hydrocephalus, etc.) or other diseases that can cause dementia (for example, hypothyroidism, vitamin B12 deficiency, or folic acid, hypercalcemia, neurosyphilis, HIV infection, severe organ pathology, etc.), as well as intoxication, including medication.
• The signs of the above cognitive impairments should be revealed outside states of confusion of consciousness.
• Anamnestic data and clinical trial data exclude the association of cognitive impairment with any other mental illness (eg, depression, schizophrenia, mental retardation, etc.).

Application of the listed diagnostic criteria allowed to increase the accuracy of the intravital clinical diagnosis of Alzheimer's disease to 90-95%, however, reliable confirmation of the diagnosis is possible only with the help of the data of the neuromorphological (usually postmortem) study of the brain.

It should be emphasized that reliable, objective information about the development of the disease plays a much more important role in comparison with numerous laboratory and / or instrumental methods of investigation. However, none of the lifetime paraclinical studies, including CT / MRI data, has high specificity and undoubted diagnostic significance.

The neuromorphology of Alzheimer's disease has now been studied in detail.

Typical morphological signs of Alzheimer's disease:

• atrophy of the substance of the brain;
• loss of neurons and synapses;
• graiulovacuolar degeneration; 
• gliosis;
• the presence of senile (neuritic) plaques and neurofibrillary tangles;
• amyloid angiopathy.

However, only senile plaques and neurofibrillary tangles are considered as key neuromorphological signs of diagnostic significance.

Complaints by the patient or his relatives about memory and other intellectual functions, as well as data on the obvious disadaptation of the patient in professional activities and / or everyday life, should force the doctor to perform a series of consistent actions to ascertain their alleged nature.

Only a set of reliable anamnestic data, features of the clinical picture of the disease, dynamic observation of its course, with the exclusion of other possible causes of dementia by clinical and paraclinical methods [obscheomaticheskoe, neurological, laboratory and neurointraskopic (CT / MRI) examination] allow the lifetime diagnosis of Alzheimer's disease.

Questions that a doctor should ask a relative or other person who knows the patient well are primarily related to the patient's violations of various cognitive functions, primarily memory, speech, orientation, writing, counting and intellectual functions proper, as well as performing the usual types of professional and everyday activities, etc.

Disturbances in the functional activity of patients

Violations in instrumental activities:

• professional activity;
• finance;
• housekeeping;
• handling of correspondence;
• independent travel (travel);
• use of household appliances;
• hobbies (playing cards, chess, etc.).

Disruptions in self-service:

• selection of suitable clothing and ornaments;
• putting on clothes;
• hygienic procedures (toilet, hairdress, shaving, etc.).

When asking a person who knows the patient well, you should also pay attention to identifying signs of psychopathological and behavioral disorders that accompany dementia at one or another stage of its development. Find out information about the presence of various manifestations of the disease should be in the absence of the patient, as relatives can hide this information because of fears of causing a patient a psychological trauma.

[17], [18], [19], [20], [21], [22]

Psychopathological and behavioral disorders in Alzheimer's disease

Psychopathological disorders:

• affective disorders (often depressive);
• hallucinations and delusions:
• anxiety and fears;
• state of amnestic confusion.

Behavioral disorders:

• aspontaneity;
• untidiness;
• aggressiveness;
• disinhibition of drives;
• excitability; wandering;
• disturbance of the rhythm of "sleep-wakefulness".

The information obtained and the initial examination of the patient allow for the primary differentiation of the dementia syndrome-the distinction between dementia and depressive pseudodementia, as well as between dementia and consciousness disorder, which makes it possible to plan correctly the further tactics of the patient's management. If you comply with the anamnestic data and the clinical picture of the diagnostic signs of depression, the patient should be referred to a psychiatrist for clarification of the diagnosis and the appointment of antidepressants. If there is a suspicion of confusion or delirium of the patient, it is necessary to hospitalize in an emergency order to identify a possible cause of the disorder of consciousness (intoxication, including drug, acute or exacerbation of chronic somatic disease, subarachnoid hemorrhage, etc.) and emergency medical care.

After the elimination of impairment of consciousness or depression, a more detailed assessment of the cognitive abilities of the patient should be carried out - perform several simple neuropsychological tests (for example, assess the mental state on the MMSE scale and the test of drawing the clock to identify violations of the optic-spatial activity - one of the most characteristic and early manifestations of dementia syndrome of the Alzheimer's type). Detailed neuropsychological examination is necessary, as a rule, only at an early stage of the disease, when it is necessary to distinguish Alzheimer's disease from an insignificant (soft) decrease in cognitive functions or associated with aging forgetfulness.

At the initial diagnostic stage, it is also necessary to conduct a conventional physical and neurological examination and perform the necessary minimum of laboratory tests: a general blood test, a biochemical blood test (glucose, electrolytes, creatinine and urea, bilirubin and transaminases), determine the level of vitamin B12 and folic acid, thyroid hormones glands, erythrocyte sedimentation rate, to conduct studies for diagnosis of syphilis, infection with the human immunodeficiency virus (HIV).

Neurological examination of patients at the stage of mild and even mild dementia usually does not reveal pathological neurological signs. At the stage of moderately severe and severe dementia, reflexes of oral automatism, some symptoms of parkinsonism syndrome (amemia, shuffling gait), hyperkinesia, etc., are revealed.

If the suspicion of Alzheimer's disease remains after completing the diagnostic examination and performing a reassessment of cognitive functions, the patient should preferably be referred for consultation to specialists in psycho-and neuro-geriatrics.

Instrumental diagnostics

Of the instrumental methods for the diagnosis of Alzheimer's disease, the most widely used CT and MRI. They are included in the diagnostic standard when examining patients suffering from dementia, as they can identify diseases or brain damage that may be the cause of its development.

Diagnostic CT / MRI signs confirming the diagnosis of dementia of the Alzheimer's type include diffuse (frontotemporal parietal or at an early stage - temporomandibular) atrophy (decrease in volume) of the brain substance. In senile dementia, the Alzheimer's type, the white matter of the brain is also damaged in the periventricular zone and in the region of the semi-oval centers.

Diagnostically significant linear CT / MRI signs that distinguish Alzheimer's from age-related changes:

• increased interhair distance compared with the age norm; expansion of peri-hypocampal slits;
• a decrease in the volume of the hippocampus is one of the early diagnostic signs of Alzheimer's disease.
• The most diagnostically significant functional characteristics of brain structures in Alzheimer's disease:
• bilateral reduction of blood flow in temporomemporal parts of the cortex from single-photon emission computed tomography (SPECT): atrophy of the temporal lobes and a decrease in blood flow in the temporomembrane cortex according to CT and SPECT.

Dementia in Alzheimer's Disease - Diagnosis

Classification

The modern classification of Alzheimer's disease is based on the age principle.

• Alzheimer's disease with an early (up to 65 years) onset (type 2 Alzheimer's disease, presenile dementia of the Alzheimer's type). This form corresponds to classical Alzheimer's disease, and in literature it is sometimes referred to as "pure" Alzheimer's disease.
• Alzheimer's disease with late (after 65 years) onset (type 1 Alzheimer's disease, senile dementia of the Alzheimer's type).
• Atypical (combined) Alzheimer's disease.

The main clinical forms of the disease differ not only in the age of the patients at the onset of the disease (especially since the age of the appearance of the first symptoms can usually not be accurately determined), but they have significant differences in the clinical picture and the features of progression.

Atypical Alzheimer's disease, or mixed type dementia, is characterized by a combination of manifestations typical of Alzheimer's disease and vascular dementia, Alzheimer's disease and Parkinson's disease or Alzheimer's disease and dementia with Levy bodies.

[23], [24], [25], [26], [27], [28]

Dementia options

• Alzheimer's dementia
• Vascular dementia
• Dementia with Levy bodies
• AIDS-dementia
• Dementia in Parkinson's Disease
• Frontal temporal dementia
• Dementia with Pick's disease
• Dementia with progressive supranuclear palsy
• Dementia with Entington's disease
• Dementia with Kreuzfeligg-Jakob disease
• Dementia with normotensive hydrocephalus
• Dementia caused by toxic substances
• Dementia in brain tumors
• Dementia in endocrinopathies
• Dementia in case of nutritional deficiency
• Dementia with neurosyphilis
• Dementia in Cryptococcus
• With dementia in multiple sclerosis
• Dementia with Gallervorden-Spatz disease

[29], [30]

Psychological correction (cognitive training)

This type of therapy is very important for improving or maintaining the cognitive abilities of patients and maintaining the level of their daily activities.

Organization of care for patients with Alzheimer's disease and other forms of dementia in later life

It is recognized in most economically developed countries as one of the most important health problems and social assistance system. This helped create a system for providing assistance to patients with dementia and their families, the main features of which consist in the continuity of support for the patient and his family at all stages of the course of the disease and the inextricable interaction of different types of medical care and social services. This help begins to be provided by a general practitioner, then the patients are sent to various outpatient diagnostic units. If necessary, they are hospitalized in diagnostic departments of short-term stay of psycho-geriatric, geriatric or neurological hospitals. After the diagnosis is established and the therapy is prescribed, the patient receives the necessary treatment on an outpatient basis, sometimes in a day hospital under the supervision of a psychiatrist or neurologist. For a longer stay, patients are hospitalized in a psychiatric hospital only if they develop productive psychopathological disorders that are not amenable to treatment in outpatient settings (severe depression, delirium, hallucinations, delirium, confusion). If patients due to gross cognitive impairment and social disadaptation can not live independently (or if family members do not cope with withdrawal), they are placed in psycho-geriatric nursing homes with permanent medical care.

Unfortunately, in Russia there is no such system of rendering medical and social assistance to patients suffering from dementia. Patients can be examined in psychiatric or neurological (rarely in specialized psycho-geriatric) clinics or hospitals, as well as in the outpatient consulting departments of these institutions. Outpatient long-term care is provided in psychiatric dispensaries, and inpatient care is provided in geriatric departments of psychiatric hospitals or in psycho-neurological boarding schools. In Moscow and some Russian cities psychogeriatric counseling and treatment in the primary health care unit, geriatric rooms with a semi-hospital in a psychiatric dispensary and outpatient consulting and diagnostic units on the basis of a psychiatric hospital are organized.

In the initial period of the disease, patients may be dangerous to others due to disinhibition of cravings or because of delusional disorders. With the development of severe dementia, they are dangerous both to others and to themselves (accidental arson, opening of gas cranes, unsanitary conditions, etc.). Nevertheless, with the possibility of providing care and supervision, it is recommended to leave patients with Alzheimer's disease as long as possible in the usual home environment. The need to adapt patients to a new, including hospital, setting can lead to decompensation of the condition and development of amnestic confusion.

In the hospital, special importance is attached to ensuring the correct treatment of patients and care for them. Concern for the maximum activity of patients (including labor therapy, exercise therapy) helps in the fight against various complications (pulmonary diseases, contractures, loss of appetite), and proper skin care and care for the cleanliness of patients can prevent bedsores.

Dementia in Alzheimer's Disease - Treatment

Differential diagnosis of dementia in Alzheimer's disease

At the final stage of the diagnostic process, the nosological nature of the dementia syndrome is clarified. Differential diagnostics is carried out between Alzheimer's disease and age-related memory loss or a soft (gentle) decrease in cognitive function ("dubious dementia"), other primary neurodegenerative processes (Parkinson's disease, Dementia with Lewy bodies, multisystem degeneration, frontotemporal dementia Peak), Creutzfeldt-Jakob disease, progressive supranuclear palsy, etc.). It is also necessary to exclude secondary to the underlying disease of dementia. According to various sources, there are 30 to 100 possible causes of the development of cognitive impairment in the elderly (secondary dementia).

The most common causes of secondary dementia are:

• cerebrovascular disease;
• Pick's disease (temporomandibular dementia);
• a brain tumor;
• normotensive hydrocephalus;
• TBI (subarachnoid hemorrhage);
• cardiopulmonary, renal, hepatic insufficiency;
• metabolic and toxic disorders (chronic hypothyroidism, vitamin B12 deficiency, folic acid);
• oncological diseases (extra-cerebral);
• infectious diseases (syphilis, HIV infection, chronic meningitis);
• intoxication (including medication).

[31], [32], [33], [34], [35], [36]

Vascular dementia

Most often, Alzheimer's disease has to be differentiated from vascular dementia. Of particular importance in this case is the analysis of objective anamnestic information. An acute onset of the disease, previous transient disorders of cerebral circulation with transient neurological disorders or short-term episodes of obscuration of consciousness, a step-like increase in dementia, and a change in the severity of its symptoms over a relatively short period of time (even within one day) indicate a likely vascular genesis of the disease. The detection of objective signs of cerebral vascular disease and focal neurological symptoms increases the probability of this diagnosis. Vascular dementia is also characterized by the unevenness of the higher cortical lesions and the violation of subcortical functions.

To recognize vascular dementia and distinguish it from Alzheimer's disease, it is useful to use the appropriate diagnostic scales (in particular, the ischemic scale of Hachinsky). An estimate of more than 6 points on the Khachinskii scale indicates a high probability of a vascular etiology of dementia, less than 4 points in favor of Alzheimer's disease. But the most significant help in differential diagnosis with vascular dementia is CT / MRI examination of the brain. For multi-infarcted vascular dementia, a combination of focal changes in the density of the substance of the brain and a poorly expressed expansion of both ventricles and subarachnoid spaces are characteristic; for vascular dementia with encephalopathy Binswanger is characterized by CT / MRI signs of pronounced white matter lesions of the brain (leukoaraiosis).

Pick's disease

Delimitation from Pick's disease (temporomandibular dementia) is based on certain qualitative differences in the structure of the dementia syndrome and the dynamics of its development. In contrast to Alzheimer's disease in Pick's disease, early personal development changes with aspiration, impairment of verbal and motor activity, or foolishness and disinhibition. As well as stereotyped forms of activity. At the same time, the basic cognitive functions (memory, attention, orientation, counting, etc.) for a long time remain intact, although the most complex aspects of mental activity (generalization, abstraction, criticism) are violated already at the initial stage of the development of the disease.

Cortical focal disorders also have certain characteristics. Violations of speech predominate, not only mandatory, but also early manifestations of the disease. There is a gradual depletion of it, a decrease in speech activity to "apparent dumbness," or verbal stereotypes, stereotypical statements or stories of "standing revolutions," which in the late stages of the disease are the only form of speech. In the late stages of Pick's disease, complete destruction of the speech function (total aphasia) is characteristic, whereas the symptoms of apraxia appear rather late and usually do not reach the severe degree characteristic of Alzheimer's disease. Neurological symptoms (with the exception of amy- mia and mutism) are usually absent even in the late stages of the disease.

Neurosurgical diseases

Great importance is attached to the timely delimitation of Alzheimer's disease from a number of neurosurgical diseases (volumetric brain formations, normotensive hydrocephalus), since the erroneous diagnosis of Alzheimer's disease in these cases does not allow timely use of the only surgical method of treatment that can be saved for the patient.

A brain tumor. The need to distinguish Alzheimer's disease from a brain tumor usually arises when, in the early stages of the disease, certain cortical disorders predominate, outstripping the rate of progression of memory impairment and intellectual activity proper. For example, the corresponding differential diagnosis should be carried out if, with relatively unexpressed dementia, severe speech disorders occur, while other higher cortical functions remain largely preserved and can be detected only with a special neuropsychological study, and if with poorly expressed verbal disorders and moderate cognitive a clear violation of the letter, counting, reading, and / or agnostic symptoms occur (predominantly parietal-occipital lesions cing brain regions).

When differential diagnosis is taken into account that with Alzheimer's disease there are no cerebral disorders (headache, vomiting, dizziness, etc.) and focal neurological symptoms. The emergence of cerebral and focal neurological symptoms or epileptic seizures in the early stages of the disease makes the diagnosis of Alzheimer's disease questionable. In this case, it is necessary to perform neurovisualizing and other paraclinical studies to exclude neoplasm.

Hydrocephalic dementia, or normotensive hydrocephalus, is the most well-known curable form of dementia, in which timely bypass surgery produces a high therapeutic effect and in almost half the cases removes the symptoms of dementia.

The disease is characterized by a triad of disorders: gradually progressive dementia, gait disturbances and urinary incontinence, the latter two signs appearing, in contrast to Alzheimer's disease, at relatively early stages of the disease. However, in some cases, not all symptoms of the "triad" can be presented evenly. As a rule, intellectual-mnestic disorders in normotensive hydrocephalus are manifested by memory and memory disturbances in recent events, as well as by impaired orientation, whereas in Alzheimer's disease they are usually more total (they suffer not only memorization and memory of recent events, but also past knowledge and experience).

In contrast to the emotional safety of patients with Alzheimer's disease with early onset, indifference, emotional dullness, and sometimes disinhibition are typical for patients with normotensive hydrocephalus. In patients with normotensive hydrocephalus, there are usually no disturbances in praxis and speech, a peculiar gait arises (slow, on stiff, widely spaced legs).

Indications for consultation of other specialists are determined depending on the patient's concomitant diseases. If you suspect a brain tumor, normotensive hydrocephalus, subarachnoid hemorrhage, a neurosurgeon's consultation is necessary.

After completion of the diagnostic examination, it is necessary to determine the functional stage (severity) of dementia due to Alzheimer's disease, using, for example, the scale of assessing the severity of dementia or the scale of general deterioration of cognitive functions. After that they develop the tactics of patient management and, first of all, choose the most appropriate and accessible form of drug treatment for them, and also evaluate the possibility of using rehabilitation methods (cognitive and functional training, creation of "therapeutic environment", etc.).

Treatment of dementia in Alzheimer's disease

Since until now the etiology of most cases of Alzheimer's disease has not been established, etiotropic therapy has not been developed. The following main directions of therapeutic effect can be singled out:

• compensatory (substitution) therapy, which is aimed at overcoming the neurotransmitter deficiency;
• Neuroprotective therapy - use of drugs with neurotrophic properties and neuroprotectors; correction of violations of free radical processes, as well as calcium and other metabolism;
• anti-inflammatory therapy;
• psychopharmacotherapy of behavioral and psychotic disorders;
• psychological correction (cognitive training).

Compensatory (substitution) treatment

Compensatory therapeutic approaches are based on attempts to replenish neurotransmitter deficiency, which is assigned the leading role in the pathogenesis of memory impairments and cognitive functions.

[37], [38], [39], [40], [41], [42], [43]

Cholinergic therapy

The most effective approach in the cholinergic therapy of Alzheimer's disease is based on the use of inhibitors of acetylcholinesterase.

Ipidacrin is a domestic inhibitor of acetylcholinesterase, which also has the ability to activate the conductivity of nerve fibers. The drug improves the intellectual and mnestic functions (based on the results of the test evaluation), increases the spontaneous activity of the patient with a simultaneous positive effect on the organization of behavior, reduces manifestations of irritability, fussiness, and in some patients - also manifestations of amnestic confusion. The initial daily dose is 20 mg (in two doses), then it is increased for 2-4 weeks to therapeutic (40-80 mg / day in two doses). The duration of the course treatment should be at least 3 months. It is necessary to control the heart rate because of the possibility of developing a bradycardia.

Rivastigmine is a representative of a new generation of acetylcholinesterase inhibitors, a pseudo-reversible inhibitor of carbamate-type acetylcholinesterase, which has a selective effect on acetylcholinesterase in the central nervous system. The drug is recommended for use in the treatment of patients with mild and moderate dementia of the Alzheimer's type. A special feature of the drug is the selection of the optimal individual therapeutic dose (the maximum dose tolerated in the range of 3 to 12 mg / day in two doses). The optimal therapeutic dose is selected by a gradual monthly increase (3 mg per month) of the initial dose, which is 3 mg / day (1.5 mg in the morning and in the evening). The drug can be combined with other medicines, often necessary elderly patients. The duration of therapy should be at least 4-6 months, although in most cases (with good tolerability and efficacy), a long-term drug intake is necessary.

Currently in the US, Canada and in a dozen countries in Europe for the first time registered a new dosage form for cholinesterase inhibitors - the Excelo patch (transdermal therapeutic system containing rivastigmine).

Use of the Excelon patch allows maintaining a stable concentration of the drug in the blood, while the tolerability of treatment improves, and more patients can receive the drug at therapeutic doses, which in turn leads to improved efficacy. The patch is pasted on the skin of the back, chest and shoulder girdle, thus providing a gradual penetration of the drug through the skin into the body for 24 hours.

The severity and frequency of side effects from the gastrointestinal tract, often noted with the use of drugs of cholinesterase inhibitors, with the use of the Excelon patch are significantly reduced: the number of reports of the occurrence of nausea or vomiting is three times less than when using Exelon in capsules. The effect of the Exelon plaster is comparable to that of Excellone in capsules at the highest doses, the target dose of the drug (9.5 mg / 24 hours) was well tolerated by the patients.

A unique drug delivery system provides a much simpler way of administering the drug to both the patient and the caregiver, and it helps to improve efficiency by quickly reaching an effective dose with minimal adverse events. When using a patch, you can easily control the process of obtaining the patient's treatment, and the patient, in turn, continues to lead a habitual lifestyle.

Galantamine is an acetylcholinesterase inhibitor with a dual mechanism of action. It enhances the effects of acetylcholine not only through reversible inhibition of acetylcholinesterase, but also through the potentiation of nicotinic acetylcholine receptors. The drug is registered for the treatment of patients with mild and moderate dementia in Alzheimer's disease. The recommended therapeutic doses are 16 and 24 mg / day in two doses. The initial dose - 8 mg / day (4 mg in the morning and in the evening) is prescribed for 4 weeks. With good tolerance from the 5th week, the daily dose is increased to 16 mg (8 mg in the morning and in the evening). With insufficient effectiveness and good tolerance from the 9th week of treatment, the daily dose can be increased to 24 mg (12 mg in the morning and in the evening). The duration of treatment should be at least 3-6 months.

[44], [45], [46], [47], [48], [49], [50], [51], [52]

The use of reminol (galantamine) for the treatment of dementias

Galantamine (Reminil) refers to a new generation of acetylcholinesterase (AChE) inhibitors with a unique dual mechanism of action that includes inhibition of AChE and allosteric modulation of nicotinic cholinergic receptors, which enhances the action of acetylcholine on nicotinic receptors.

Experimental studies have shown that galantamine possesses neuroprotective properties, which are realized through a-nicotinic acetylcholine receptors. It protects neurons from the neurotoxic effects of glutamate and beta-amyloid in vitro and increases their resistance to anoxia.

Galantamine (Reminil) causes a positive therapeutic effect in Alzheimer's disease and mixed dementia. In domestic and foreign clinical trials, the drug has been shown to improve cognitive function and behavior in patients with mild to moderate dementia.

The effect of galantamine in mixed dementia was evaluated in numerous trials. Good tolerability of galantamine and relative stability of cognitive impairment during long-term therapy (24-36 months) in elderly patients with mixed dementia are also shown. There is evidence that the primary improvement in cognitive functions persists for at least a year.

In a double placebo-controlled trial, M. Raskind et al. (2004), in studying the efficacy of galantamine in patients with Alzheimer's disease under long-term therapy (36 months), it was found that with a mild to moderate dementia in 80% of cases, the rate of progression of dementia slows down by approximately 50% compared with the placebo group. Thus, galantamine significantly delays the progression of Alzheimer's disease.

The sooner the therapy with dementia with galantamine begins, the better the prognosis, which indicates the importance of its timely diagnosis. In various studies, it was noted that in patients receiving continuous pharmacological treatment from the onset of the disease, the overall long-term prognosis is better.

It is also proved that after 5-month therapy with galantamine, the daily activity of patients on the ADL scale significantly improves, and this does not depend on the initial level of dementia.

Galantamine therapy not only improves the quality of life of patients, but also facilitates care for them, reduces the burden, including psychological, on the guardian. The data are supported by the results of the work, in which the effect of galantamine on behavioral disorders was analyzed. It has been established that galantamine therapy slows the progression of Alzheimer's disease and mixed dementia. He is well tolerated by patients, allowing to significantly reduce the burden on the relatives of the patient associated with caring for him, and to reduce the cost of treatment. He is reasonably considered the drug of the first choice in the treatment of Alzheimer's dementia. 

Donepezil - a derivative of piperidine - is highly specific, an inhibitor of central acetylcholinesterase with a high bioavailability "and a long half-life, which allows prescribing the drug once a day. Its effectiveness was confirmed in multicenter, double-blind, placebo-controlled studies in patients with mild to moderate dementia. Treatment begins with a dose of 5 mg 1 time per day (evening), with good tolerability after 4 weeks, the daily dose is increased to 10 mg (once in the evening). The duration of therapy should be 3 months or more before the "exhaustion" of the therapeutic effect.

Glutamatergic therapy

In recent years, convincing evidence of involvement in the neurodegenerative process underlying Alzheimer's disease, not only cholinergic, but also other neurotransmitter systems, primarily glutamatergic, has been obtained.

Memantine is a modulator of the glutamatergic system, which plays an important role in learning and memory processes, which has neuroprotective activity. He successfully passed clinical trials in Russia, as well as in the US and several European countries. The drug is indicated for the treatment of patients with mild to moderate and severe dementia in the presence of Alzheimer's disease. In addition to improving cognitive functions, the drug has a positive effect on motor disorders, leads to an increase in the level of spontaneous activity of patients, improving concentration and increasing the pace of intellectual activity.

Patients with severe dementia improve their self-service skills (using the toilet, eating, taking care of themselves), reducing the severity of behavioral disorders (aggression, anxiety, apathy). A good tolerability of the drug and no serious side effects have been established. Its daily dose is 20 mg (10 mg in the morning and in the afternoon). Treatment begins with a dose of 5 mg (once in the morning), every 5 days, the daily dose is increased by 5 mg (in two doses) until the therapeutic dose is reached. The course of treatment should be at least 3 months.

Nootropics

When using pyracetam, pyrithinol, improving metabolism in the brain and cognitive functions due to stimulation of acetylcholine release, no reliable positive results were obtained in the treatment of Alzheimer's dementia. Moreover, the administration of large doses of these drugs may have a negative effect due to possible neurotransmitter depletion.

Vascular medications

There were no reliable data on the therapeutic effects of vascular drugs until recently. However, in the study of the clinical efficacy of nicergoline in Alzheimer's disease, a statistically significant improvement in the status of patients according to the indices of three different scales after 6 and 12 months of its administration was established. The therapeutic effect of the drug is associated with its ability to increase cerebral blood flow and improve energy metabolism in the hungry brain. In standard doses (30 mg / day, 10 mg 3 times a day) the drug did not cause serious side effects, Nicergoline recommended to be prescribed as a means of additional therapy in patients of the most senior age and in the presence of combined Alzheimer's and vascular dementia.

Neurotrophic drugs

Based on the evidence obtained in the last decade of involvement in the pathogenesis of primary neurodegenerative diseases (primarily Alzheimer's disease) deficiency of neurotrophic growth factors, a neurotrophic therapy strategy has been developed. Since it was found that the growth factor of the nervous tissue and some other neurotrophic growth factors interfere with the development of apoptosis of brain cells, the use of neurotrophic drugs is of great importance in the neuroprotective therapy of Alzheimer's disease. They, on the one hand, enhance the functional activity and protection of still intact neurons and synapses, and on the other - improve cognitive functions. Despite significant experimental advances in this field, there are no available drugs for peripheral administration containing neural tissue growth factor and able to penetrate the blood-brain barrier.

Cerebrolysin

The discovery of neurotrophic effects of cerebrolysin, similar to the activity of the growth factor of the neural tissue, aroused a new interest in this drug, which for many years was widely used in neurology for the treatment of stroke and other forms of cerebrovascular diseases. Cerebrolysin consists of amino acids and biologically active neuropeptides with a low molecular weight. It regulates the metabolism of the brain, shows neuroprotective properties and unique neuron-specific activity. The drug slows the process of abnormal amyloidogenesis, prevents the activation of neuroglia cells and the production of inflammatory cytokines, inhibits apoptosis of brain cells and promotes the formation of stem cells (neuronal precursors), dendritic growth and the formation of synapses, thus inhibiting the pathogenetic mechanisms leading to neurodegeneration and neuronal death in Alzheimer's disease.

In contrast to the growth factor of the nervous tissue, the cerebrolysin oligopeptides easily overcome the blood-brain barrier, having a direct effect on the neuronal and synaptic systems of the brain in conditions of peripheral administration of the drug.

The effectiveness of course therapy with cerebrolysin for the treatment of Alzheimer's disease with intravenous administration of 20-30 ml of the drug in 100 ml of 0.9% sodium chloride solution (for a course of 20 infusions) is proved. The initial dose of the drug is 5 ml per 100 ml of 0.9% sodium chloride solution; then over the next 3 days it is gradually increased (by 5 ml daily) to the recommended therapeutic dose. Course treatment with cerebrolysin 1-2 times a year is included in the complex of combined pathogenetic therapy for patients with mild and moderately demented dementia in Alzheimer's disease in combination with cholinergic or glutamatergic drugs.

[53], [54], [55], [56], [57], [58], [59]

Antioxidants

Oxidative stress is now considered as one of the main causes of the development of various neurodegenerative processes, including Alzheimer's. In the development of antioxidant therapy in Alzheimer's disease, there are two alternative directions: the use of "external" antioxidants (exogenous or endogenous origin) and stimulation of intracellular antioxidant systems. The study of the effectiveness of a number of "external" antioxidants (vitamin E and its synthetic analogs, extract of the leaves of ginkgo bilobate, selegiline, etc.) did not lead to unambiguous results.

[60], [61], [62], [63], [64], [65]

Anti-amyloid therapy strategies

Anti-amyloid therapy directed to the key pathogenetic mechanism of Alzheimer's disease (abnormal amyloidogenesis) is currently still under development or clinical research.

The main directions of therapy:

• reduction of beta-amyloid formation from the precursor protein;
• slowing the transition of beta-amyloid from soluble to aggregated (neurotoxic) form;
• elimination of beta-amyloid aggregates with neurotoxic properties.

The idea of reducing the content of beta-amyloid in the brain by repeated immunizations of APP-transgenic mice with serum containing human beta-amyloid is the basis for a fundamentally new direction in the development of anti-amyloid treatment of Alzheimer's disease. Such immunization leads to the production of antibodies to beta-amyloid, which can contribute to the removal of deposits of this protein from the brain. Another approach is associated with the peripheral administration of anti-beta-amyloid peptide antibodies (passive immunization).

[66], [67], [68], [69], [70], [71], [72],

Anti-inflammatory and hormone replacement therapy

Anti-inflammatory (non-steroidal anti-inflammatory drugs) and hormone replacement therapy (estrogen preparations) are still in the stage of clinical study. The basis for the development of appropriate therapies has been epidemiological data suggesting that patients with long-term anti-inflammatory (non-steroid) or estrogenic drugs significantly less likely to develop Alzheimer's disease.

Because of productive psychopathological disorders and behavioral disorders, difficulties can arise in examining patients, performing therapeutic and rehabilitation measures and caring for patients, so their treatment becomes particularly important.

Psychopathological and behavioral symptoms are more likely than cognitive impairment to serve as an indication for the hospitalization of patients with Alzheimer's disease. Behavioral disorders (aimless activity, attempts to leave home, aggression, etc.) significantly worsen the quality of life of both patients and carers, and also statistically significantly increase the cost of maintaining patients.

In the treatment of patients with dementia, it is extremely important to correctly assess the origin of psychotic symptoms, in particular, the state of confusion. Delirium, confusion and other psychotic states of exogenous type usually develop in demented patients with additional effects, most often with intercurrent somatic diseases or with exacerbation of chronic diseases, as well as as a result of drug or other intoxications. Each case of occurrence of disorders of exogenous type requires an obligatory thorough (with the necessary clinical and laboratory studies) to ascertain its cause and its elimination by appropriate medical measures.

[73], [74], [75], [76], [77], [78], [79]

Diagnosis of mental disorders and treatment of patients

In Alzheimer's disease, psychopharmacological drugs should be used with great care. Inadequate prescription of psychotropic drugs can cause weighting of the symptoms of dementia and even the development of amnestic confusion. Most often such effects are accompanied by the use of drugs with anticholinergic action [eg, tricyclic antidepressants (TA)], as well as neuroleptics, beta-adrenoblockers, benzodiazepines and sedative hypnotics, so avoiding (if possible) the appointment of such drugs is one of the principles of drug treatment of Alzheimer's disease .

Neuroleptics should be used only in patients with severe behavioral or psychotic symptoms, and it is possible to prescribe drugs that do not possess a cholinergic effect. TA patients are contraindicated, and benzodiazepine derivatives, including hypnotics, can be prescribed for a short time. Only with pronounced aggressiveness neuroleptics are used: 20-100 mg / day of thioridazine is prescribed as monotherapy or in combination with serotonin reuptake inhibitors. Short-term appointment of haloperidol (2.5 mg intramuscularly 2 times a day) is possible only in hospital with a pronounced excitation and aggression (no more than 3-5 days).

Atypical antipsychotics have significant advantages over traditional antipsychotics, since they do not cause extrapyramidal and cholinergic side effects at low but clinically effective doses for elderly patients.

Risperidone is prescribed in a dose of 0.5 mg to 1 mg / day. If necessary, the dose can be increased to 1.5-2 mg / day (in 2 doses). Quetiapine is prescribed in a dose of 25 to 300 mg / day (the optimal dosage is from 100 to 200 mg / day) in two doses. (Morning, evening).

These drugs are prescribed for 3-4 weeks, after the cessation of psychotic and behavioral disorders gradually (for 1-2 weeks) reduce their doses, and then cancel. If, on the background of the cancellation or reduction of the dose, the psychotic symptoms appear again or increase, the treatment is continued at the previous therapeutic dose.

[80], [81],

How to prevent dementia in Alzheimer's disease?

Prevention of Alzheimer's disease is not currently developed. The risk factors for its development include late age, secondary cases of dementia of the elderly in the family, the presence of the gene apolipoprotein E; to the possible factors - TBI and thyroid disease, low level of education and late age of the mother at the birth of the patient; to the presumptive factors - a prolonged impact of stress factors, an increase in the concentration of aluminum in drinking water.

Smoking, prolonged use of non-steroidal anti-inflammatory drugs and estrogens, as well as regular consumption of alcohol in small doses can act as factors that reduce the likelihood of the disease.

The course and prognosis of dementia in Alzheimer's disease

The natural course of Alzheimer's disease is characterized by a steady decline in cognitive and "non-cognitive" functions. From the moment of diagnosis of the disease to death, an average of 9 years, but this indicator is extremely variable. Ultimately, the patient is bedridden and requires complete care. Death often comes from intercurrent illnesses (for example, pneumonia). Faster deaths occur in older people, men, patients with a more severe disruption of daily life activity, more severe dementia, and with more severe aphasia. Race, marital status, level of education do not have a significant effect on survival. Algorithms have been developed that, based on clinical data, can predict the life expectancy or the time when a patient needs to be placed in a nursing facility. They also make it possible to assess the effect of pharmacotherapy on the survival and quality of life of the patient.