RU2478209C1 - Diagnostic technique for parkinson disease in patients with olfactory dysfunction - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: what is presented is a diagnostic technique for Parkinson disease in the patients with olfactory dysfunction. The suffered acute respiratory viral infection accompanied by hyperthermia is followed by stating the olfactory dysfunction. An examination complex containing determining alleles IL-1β(-511) "2/2", "1/2", HLA-DRA rs3129882 SNP, higher induction of IL-iβ production, polysomnography findings is used. If observing a carriageship of alleles IL-lβ(-511) "2/2", "1/2", HLA-DRA rs3129882 SNP, higher serum cytokine production, REM-sleep behavioral disorder, in the patients with hypo or anosmia, Parkinson disease is diagnosed.

EFFECT: invention provides diagnosing Parkinson disease at the early stages of the disease.

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Description

The invention relates to medicine, namely to otorhinolaryngology, and can be used for early detection of Parkinson's disease.

In 1817, James Parkinson in his book "Essays on trembling paralysis" described the disease, later named after him - Parkinson's disease (hereinafter - PD), and in 1877 J. Sharko supplemented the clinical characteristics of the disease.

To date, the origin of Parkinson's disease remains not fully understood. Parkinson's disease is often a disease of the elderly, often develops at the age of 70-80 years. However, in recent decades, Parkinson's disease has steadily "become younger", and therefore, there are frequent cases of Parkinsonism in the sixth decade of life, and even earlier.

It is known that the incidence of PD is growing every year faster than the population is aging, affecting about 1 out of 1000 people over the age of 55, and at the age of 65 and over 1 out of 100 suffers from Parkinson's disease. Only in 20% of cases it is possible to diagnose the disease before the age of 50 years and 0.8-10% to 40 years.

The disease is based on the progressive degeneration of neurons producing dopamine and other monoamines in certain parts of the central nervous system, as well as in the peripheral nerve ganglia of the internal organs (gastrointestinal tract, etc.).

Recognition of the initial manifestations of the disease is extremely rare. The onset of the disease develops subclinically and may take several years before the first symptoms of this ailment appear. To date, there are no tests, tests that can reliably diagnose Parkinson's disease comprehensively at the pre-clinical stage.

Scientists all over the world are searching for an algorithm for the early diagnosis of Parkinson's disease and other forms of Parkinsonism, which have common features, in order to select adequate preventive measures to slow down the development of a disabling disease by prescribing appropriate treatment.

It is known from practice that in the subclinical period of Parkinson’s disease there are no vivid symptoms characteristic of the stage of the disease’s height, and accordingly the number of motor neurons dead is not so great as to cause symptoms such as muscle stiffness, tremor, stiffness of movements, imbalance, masked facial expression etc.

During the height of Parkinson’s disease, symptoms such as impaired gastrointestinal motility, weakness, sleep disturbance such as daytime drowsiness and insomnia, impaired smell function, depression, anxiety, restless legs syndrome, urination disorders, sexual dysfunction, orthostatic hypotension, tremor rest, bradykinesia, muscle stiffness, postural disorders and other symptoms resulting from progressive degeneration of nerve cells.

Parkinson's disease belongs to the group of disabling diseases and can develop from a few months to a dozen years, manifesting itself as severe changes in the motor sphere or minor violations thereof.

Despite significant progress in the field of medicine, the diagnosis of Parkinson's disease in the early stages of development is currently a difficult task due to the lack of specific laboratory diagnostic criteria to establish the correct diagnosis at the initial stage.

Since this disease has a peculiarity when progressing to bring the patient into a state of disability - helplessness, the classical method for diagnosing PD has a significant drawback due to the fact that the clinical symptoms of PD develop with the degeneration of 80% or more neurons of the substantia nigra, and this process is irreversible and steadily leads to the death of the patient.

Therefore, the task of finding early diagnostic criteria and developing new schemes for the prevention of Parkinson's disease is relevant.

The problems of diagnosing PD at an early stage arise not only due to soft manifestations during the onset of a disease originating at the cellular level, but also because of the complexity of the anatomical structures of the nervous system.

In the pathological process, changes occur in neurons, which lead to impaired function of the organs controlled by this end section of the nervous system.

The most promising way to diagnose Parkinson's disease early is to evaluate non-motor manifestations such as smell, sleep, etc.

It is known that hair cells are located at the end of the peripheral process of the olfactory cell of the olfactory nerve and are highly differentiated peripheral neurons located in the thickness of the mucous membrane of the superior turbinate.

The olfactory mucosa covers an area of about 2 cm ² in the apex of each nasal cavity and extends towards the upper nasal concha and nasal septum.

When the Bowman glands, aromatic substances dissolved in the secretion penetrate into the upper nasal passage, the olfactory receptors (bipolar neurons) are excited through the receptive surface of the hair cells.

Further, excitation, like centrifugal force, is transmitted through complexes of axons that form filaments (fila olfactoria) visible to the eye to the brain through the openings of the ethmoid bone plate, joining the olfactory bulb (bulbus olfactorius).

It is known that the speed of impulses along these nerves is the lowest in comparison with other nerve trunks. The first neuron comes into contact with the second neuron - mitral cells of the olfactory bulb, which is a protrusion of the terminal brain (telencephalon).

The olfactory bulb can be located, partially plunging into the nasal cavity, posteriorly passing into the olfactory tract (tractus olfactorius), passing in the groove of the same name (sulcus olfactorius). The axons of the second neuron partially form a synaptic connection with the third neuron (olfactory tract), continuing, flattening, into the olfactory triangle or tubercle (trigonum, s.tuberculum olfactorium), adjacent to the anterior perforated substance (substantia perforata anterior).

Trigonum olfactorium mainly consists of nerve cells, on which some of the olfactory pathway fibers end.

In the olfactory triangle, divided into three olfactory strips, the fibers in various ways reach the cortical end of the olfactory analyzer - the hook, uncus (convolutions near the ammonian horn). The second and third neurons of the olfactory tract are recognized as “primary” centers of smell.

It is known that olfactory hairs, cord, tubercle in their morphological structure and origin are part of the cerebral cortex. This fact has significant diagnostic value in the differentiation of diseases of the nervous system.

The axons of the third neurons and partially of the second, bending around the corpus callosum above and below, go to the secondary cortical olfactory centers, which include the gyrus of the mediobasal surface of the temporal lobe (parahippocampus and pear-shaped) and ammon horn (hippocampus) entering the old bark.

Ammon horn is one of the important structures of the limbic system and is considered the most epileptogenic part of the brain. In pathological processes, seizure-like conditions occur, characterized on the electroencephalogram by synchronized discharges of bioelectrical activity.

Attacks can also consist of short absences or like conditions, feelings of alienation, transient macro- and micropsy, experiencing dejavu and transient depressions, sometimes accompanied by impaired smell, as well as oral movements, the assessment of topical symptoms is also of significant diagnostic value.

Then the three olfactory strips continue their movement to the cortical end of the olfactory analyzer: lateral to the amygdala, corpus amygdaloideum; intermediate in the nerve cells of the anterior perforated substance, substantia perforate anterior and medial is directed to the medial surface of the hemisphere, under the beak of the corpus callosum.

From here, some fibers go to septum pellucidum, and then along the fornix and fimbria hippocampi reach the cortical end of the olfactory analyzer, other fibers go as part of the striae longitudinales mediates and also reach the olfactory analyzer (uncus) along the ligamentous and dentate gyrus.

The connection of the olfactory centers with each other by the collaterals is of great clinical diagnostic value, especially significant during the rehabilitation of patients.

Thus, the olfactory zone, located in the region of the superior nasal concha, is a single whole with cortical centers. Violation of anatomical structures in any zone leads to the development of dysfunction of the sense of smell.

It was previously known that hyposmia or anosmia can be the result of various pathological conditions involving the olfactory zone, and in the absence of changes from the side of the nasal cavity and paranasal sinuses, there is a natural need to exclude neurological disorders.

However, in a classic neurological examination of patients with impaired sense of smell, a search for “gross” changes on the part of the central nervous system is performed, and in the absence of such, a diagnosis is made - hypo- or anosmia of unclear etiology.

Studies of the Pacific Research Institute of Health in Honolulu have shown a possible association of hypo- or anosmia with degenerative processes in the extrapyramidal system and may be early symptoms of PD.

Parkinson's disease, related to synucleinopathies, is characterized by the accumulation of alpha-synuclein protein and the formation of threadlike structures with a diameter of 20-40 nm inside glial cells.

The concept of Braak et al. in Parkinson’s disease, explains the ascending type of pathological neuro-degenerative process - from the caudal sections of the brain stem (subtle changes in projection neurons and the structures of the olfactory complex) to the cerebral cortex.

The premotor stage of the disease can take up to 8 years.

By the time the symptoms manifest, neurodegeneration, which is non-linear, is developing rapidly, causing the death of most of the neurons. In connection with this statement, it is obvious - attempts at neuroprotection at a later stage cannot be successful.

Studies of the Pacific Research Institute of Health about hypo- and anosmia can be presented as an early symptom of Parkinson’s disease, which appears before the development of the main symptoms in 2-8 years, but the drawback of this method is only the assumption about the possible development of the disease, as well as the reliability of this method diagnosis, since a violation of olfactory function may accompany other pathological conditions, as well as the question of an ascending pathological process remains a debate nym, because the neuro-degenerative changes in the nervous system are common - the system and can not occur in isolation in a separate portion of the nerve fibers or groups of neurons.

The process of damage to the nervous system in Parkinson's disease occurs slowly with the involvement of an increasing number of nerve cells. The cells affected by degeneration lose their function, therefore, the less cellular elements are present in the organ, the faster its function will be lost in the development of pathology.

Olfactory cells, as well as other neurons that are affected in the early stages of Parkinson's disease, lose their functional activity, while the loss of smell occurs gradually with a change in the sensitivity threshold of aromatic substances.

When studying and evaluating the olfactory analyzer, it is necessary to take into account that in the process of ontogenesis there are changes in its function, which cannot be regarded as a pathology.

As early as 1904, Vashid revealed with a osmoesthesiometer a significant decrease in olfactory function during aging. Further studies confirmed this observation, but noted not the same dynamics of the threshold of olfactory function in all age groups and determined the dependence on gender, so women had a sharper sense of smell than men.

According to A.I. Bronstein, the severity of smell increases by the age of 6, then there is a gradual decrease and, by old age, fading. The olfactory system becomes most functional during puberty until about 45 years old, and the decline begins at 45-50 years of age and a particularly sharp decrease is noted at 70 years of age. This fact must be taken into account when evaluating the smell function.

A.I. Bronshtein, one of the first, proposed a methodology for the study of smell using a set of 8 odorous substances in a certain sequence from the weakest No. 1 to the strongest No. 8 (Babiyak V.I., Nakatis Y.A., “ Occupational diseases of the upper respiratory tract and ear ”, Hippocrates, 2009, p. 342).

Aromatic substances were arranged in the following sequence: laundry soap, rose water, bitter almond water, tar, turpentine, 10% aqueous ammonia solution, acetic acid, and chloroform. It was found that aromas No. 1-5 are perceived by the olfactory nerve, 6 and 7 olfactory and trigeminal, and the 8th olfactory and glossopharyngeal nerves.

This diagnostic method allows you to differentiate a number of diseases in which the olfactory nerve is turned off and the functions of the trigeminal and glossopharyngeal nerves are preserved, while the patient often confuses aromas, perceiving them in a distorted form.

This method to this day is considered unique and only improved by scientists around the world, in order to determine more subtle - threshold changes in the sensation of smell, which can be used, for example, to diagnose Parkinson's disease.

One can evaluate the olfactory threshold, the ability to distinguish and identify odors.

Sleep disturbance by type of daytime sleepiness, insomnia and restless legs syndrome are manifestations of PD in 19% of cases.

Therefore, the study of sleep patterns in patients with hypo- and anosmia is relevant.

In PD, the most common parasomnias include motor activity in sleep, periodic limb movements, night myoclonia, nightmares, night hallucinations, panic attacks, etc.

Psychomotor agitation in a dream can be manifested by speaking, groans, screaming, movements of the limbs and trunk, often active. During nightmares, patients are able to perform protective actions, manifested by blows to their hands, feet, etc.

Parasomnia that occurs no earlier than the 90th minute after falling asleep can not last long and when the patient wakes up, as a rule, he is in clear consciousness without losing orientation in time and space.

Motor activity in a dream can occur against the background of a lack of muscle atony, developing in a dream, during which a person sees dreams. While normal muscle atony blocks any movement (with the exception of eye movements or individual muscle twitches) even during nightmares.

Providing muscle atony is carried out by the interaction between the structures of the pedunculopontine nucleus and the bulbospinal inhibitory zone. Bulbospinal inhibitory zone through the glycineergic pathway causes active inhibition of motor neurons of the anterior horns.

Disruption of the connections of the pedunculopontine nucleus, due to degeneration of glutamatergic neurons, with the medial segment of the pale ball or the bulbospinal zone leads to the appearance of motor activity during dreams.

Sleep and wakefulness disorders may be early non-motor manifestations of the onset of Parkinson's disease (20%).

However, these disorders are practically not diagnosed and, as a rule, the patient associates this condition with overwork, increased physical activity, stress, etc., thereby underestimating the importance of these symptoms for early diagnosis of the disease.

Chaudhuri K.R. et al. found that sleep disorders are based on structural and functional disorders in the system of descending connections of hypothalamic neurons with dopaminergic neurons of the ventral casing, as well as ascending trunk-thalamo-cortical projections. Disorders of neurotransmitter systems (noradrenergic, serotonergic, acetylcholinergic, glutamatergic) due to degeneration of the brain stem nuclei play one of the decisive roles in the pathophysiology of sleep and wakefulness.

Parkinson's disease is characterized by disturbance of night sleep, alternating with daytime sleepiness, increasing with increasing duration of the disease, as well as the presence of symptoms of akathisia, sensory disturbances, nocturia, night and morning dystonia, morning tremor and restless legs syndrome.

The method of polysomnography allows one to trace various changes in the functional systems of the body during sleep (VB Dorokhov, Institute of Higher Nervous Activity and Neurophysiology RAS, Moscow; Human Physiology, 2002, v. 28, No. 2, pp. 105-112).

Printing registration of various physiological and behavioral indicators of activity is a unique experimental approach for studying the relationship between the brain, various body systems and the human psyche. The polysomnographic survey method became possible due to the rapid development of computer technology.

Diagnosis of sleep disorders is carried out at night.

The method is based on the simultaneous registration of a large number of physiological parameters.

A standard polysomnographic study provides for the collection and analysis of information about: a) the patient’s sleep structure, b) the patient’s breathing patterns, c) cardiac activity, d) arterial blood oxygenation.

In a polysomnographic examination, three successive stages can be distinguished:

1. Registration of data. Polysomnographic examination includes video monitoring and recording of more than 20 parameters: electroencephalograms (EEG); electrooculograms (EOG); electromyograms (EMG); oronasal airflow; chest and abdominal breathing efforts; electrocardiograms (ECG); arterial blood saturation (SaO ₂ ); Actogram and other indicators.

2. Data analysis. Analysis of PSG recordings and determination of sleep stages is carried out manually (manually) or automatically according to special algorithms in accordance with the criteria proposed by a group of experts led by A.Rechtschaffen and A.Kales.

When analyzing PSG records, it is divided into epochs lasting 30 seconds and for each epoch the stages of sleep are successively determined. The results of constructing a sleep profile are presented in the form of a hypnogram, on which in a compressed form you can see the dynamics of the stages of sleep.

Computer programs have algorithms that automatically detect individual physiological patterns (events) that are important for describing sleep, and then build a computer profile of sleep based on the selected patterns. The histograms for these events provide additional information about changes in the physiological systems of the body at different stages of sleep. The results of automatic recognition of events important for the description of sleep are presented in the form of histograms and stored in a separate file in text format.

3. Clinical conclusion. Based on the results of the analysis, PSG records write a clinical report. There are generally accepted indicators that should be reflected in the text of the conclusion. The presence in the program of the possibility of creating an automated conclusion significantly speeds up its writing and allows you to include in the conclusion the detailed results of quantitative data analysis.

For automatic recognition of the functional states of the body, there are two possibilities for creating a new algorithm based on algorithms for automatically determining the stages of sleep.

The first method is quite laborious, as it requires a long setup of recognition algorithms.

The second method is simpler - to create a new algorithm, part of the record is processed manually, and on the basis of the received sample, the program automatically creates a new computer algorithm for a particular subject. Experience has shown that the quality of automatic analysis in this case is quite high and almost does not differ from manual analysis.

The universal capabilities of PSG polygraphs can be used to diagnose sleep pathologies.

So, for example, using polysomnography, it is possible to identify a recently established marker of Parkinson's disease - hyperechoogenicity of the substantia nigra of the brain stem, however, the sensitivity of this method can also be noted with other extrapyramidal disorders, and therefore needs to be clarified and differentiated with other additional symptoms research methods.

It is known that with PD, the functions of the muscles of the larynx are disrupted, which sooner or later leads to hoarseness of the voice. Based on this fact, attempts at early diagnosis of the disease by voice changes have already been carried out, but have been unsuccessful.

A professor at the University of Haifa, Shimon Sapir, was able to do this by taking an alternative approach to voice analysis and developing software that identifies his characteristic changes before they become audible.

Tests of this method carried out in Israel and the USA have confirmed its effectiveness.

According to the developers, they intend to use the method for examining people with a hereditary predisposition to the disease, with the possible use of it in national screening programs.

However, the statement about early diagnosis may remain controversial, since dysfunction of the muscles of the larynx occurs with significant degenerative lesions of the nervous tissue.

Degenerative diseases of the central nervous system can be based on an infectious or autoimmune origin. Genetic and environmental factors can contribute to the development and progression of Parkinson's disease and its complications.

In the course of numerous studies, scientists have found associations of various diseases with alleles of HLA supergene loci. Later, conclusions were drawn about the possible role of the infectious factor in the development of autoimmune processes that underlie diseases of the nervous system, which may also confirm the immunogenetic version of the development of pathologies.

At the heart of the defeat of neurons of the black substance of the brain that controls motor activity is a violation of antigenic recognition and a breakdown of tolerance. The presence of certain alleles in the HLA genotype can be regarded as a factor in the development of diseases. The study of the relationships of individual alleles, haplotypes, and genotypes with the onset of various diseases made it possible to characterize additional diagnostic markers for them.

For example, the HLA-DQB 1 * 0602 allele is associated with cataplexy (catatonia) in patients with narcolepsy, and is also one of the markers of predisposition to multiple sclerosis.

The pathogenesis of autoimmune diseases depends on the generation of an autoreactive immune response. Normally, the destruction of autoreactive cells occurs by apoptotic deletion.

It is known that the frequency of an autoreactive response increases with age, although it often does not lead to pathological conditions. The emergence of autoreactive immunocytes is a necessary, but not the only condition for the development of an autoimmune disease. It should be borne in mind that only part of the influence of the genotype can be explained by the action of genes of the HLA locus, 30-50% of the total genetic contribution is made by the HLA-DR4 locus.

Rheumatoid arthritis related to systemic diseases is considered an autoimmune pathology leading to chronic joint inflammation. Rheumatoid arthritis is an HLA-B * 27 associated disease, that is, the risk of a disease rises sharply if HLA-B * 27 alleles are present in the genome.

Reactive arthritis is also today considered an HLA-B * 27 associated disease that develops after an acute intestinal or genitourinary infection.

HLA-B * 27 test - for autoimmune diseases, it is regarded as a genetic marker of predisposition. In patients suffering from inflammatory arthritis of the spine and joints, the presence of HLA-B * 27 indicates a possible development of the disease from the group of seronegative spondyloarthropathies.

This group includes ankylosing spondylitis, psoriatic arthritis and Reiter's disease. A positive test for HLA-B * 27 - with ankylosing spondylitis (ankylosing spondylitis), up to 90% of cases can be noted, however, this gene is not the only marker of a disease, but is regarded as an additional diagnostic marker in a comprehensive examination.

The absence of HLA-B * 27 in the patient’s genotype nevertheless does not guarantee protection against this pathology.

According to foreign literature, in 47-60% of patients with anterior uveitis are carriers of the HLA-B * 27 allele.

In idiopathic inflammatory myopathy - dermatomyositis, a linkage with some alleles of the HLA locus is also revealed, so the strict association of the HLA haplotype - DRB1 * 0301, DQA1 * 0501, DQB1 * 0201 in patients with myositis-specific autoantibodies, especially against histidyl synthase-T, is determined. alanyl-tRNA synthetase and tRNA, moreover, the correlation is closer with myositis-specific autoantibodies than with the disease itself. Moreover, the incidence of HLA-DMA * 0103-43%, while in healthy people only 8% and DMB * 0102 20%, compared with 3% healthy.

Autoimmune pathology, characterized by cutaneous and visceral fibrosis, systemic scleroderma, is also considered a genetically programmed disease in pathogenesis, which is important for the genes of the main histocompatibility complex. In all patients, HLA alleles are detected - DRB1 * 1602, DQA1 * 050l and DQB1 * 0301.

The haplotype was also identified by the HLA class II alleles DRB1 * 1302, DRB1 * 0604 in patients in whose body antifibrilarin (AF) is formed. Most AF-positive patients are characterized by an independent association of two alleles of the HLA-DQB1 * 0604 locus, HLA-DQB 1 * 0301, HLA-DQB1 * 0602 or HLA-DQB1 * 0302. In systemic scleroderma, as in most autoimmune diseases, the level of IL-4 expression is important, which acts as a stimulator of collagen synthesis.

In view of the presented data, it is incorrect to consider the contribution of only HLA gene alleles to the formation of diseases, including autoimmune ones. The genes of the main histocompatibility complex are located on the short arm of the sixth human chromosome (6p21.3) and induce the production of specific proteins in the body - human leukocyte antigens.

Immunogenetic studies are of great importance for practical medicine, since HLA antigens are an individual cell passport. HLA antigens are glycoproteins and are encoded only by the corresponding HLA - gene of the sixth chromosome. The individuality of this complex can be compared with fingerprints, which allow you to accurately identify a person.

The HLA typing method (FIG. 1) is considered unique throughout the world, for example, during transplantation of donor organs, complicated by the huge number of possible combinations of HLA antigens that determine strict antigenic identity.

This method can be used to diagnose the disease, however, the study is possible only in combination, since the identification of the HLA-DRA variant can be regarded as a factor in the possible development of the disease. Detection of certain gene alleles for diagnostic purposes can be used in combination with other research methods, like genetic markers.

It must be borne in mind that the clinical manifestations of autoimmune diseases are controlled by certain associations, and each type of pathology is determined by a combination of these genes.

Patients with autoimmune diseases are distinguished by a set of specific alleles of genes, however, consideration of pathology in isolation from clinical manifestations cannot be an early sign of Parkinson's disease, since the frequency of loci occurring in pathologies similar by the autoimmune mechanism may be the same. This explains the need for a comprehensive assessment of molecular genetic analyzes and objective examination data.

Researchers Find Connection between Parkinson's Disease and Immune System-Related Gene presents a new study identifying a variant of the HLA-DRA locus as a risk factor for Parkinson's disease. The data are confirmed by a survey of about 4,000 participants recruited from clinics in Oregon, Washington, New York and Georgia (http://www.ninds.nih.gov/news_and_events/news_articles/HLA_gene_parkinson_risk.htm).

A comparative immunogenetics study by Hamza et al., In a large sample of patients (2,000) and healthy donors, showed a significant association of the SNCA rs356220 SNP and HLA-DRA rs3129882 SNP genes with Parkinson's disease (Hamza et al. (2010), Nature Genetics, 15 August doi: 10.1038 / ng.642).

Studies also confirm a statistically significant increase in the DQB1 * 06 allele (p = 0.002) in Parkinson's disease, which indicates the association of the disease with the immune system.

In Parkinson’s disease, a decrease in the activity of mitochondrial complex I in platelets, as well as the level of tyrosine hydroxylase, dopamine, dopamine receptors in lymphocytes and cysteine deoxygenase in the blood plasma was revealed.

Parkinson's disease is characterized by pathomorphological changes in the nervous system, for example, degenerative changes and death of nerve cells occur in black matter and a pale brain of the brain, Levy bodies are found in the cytoplasm of neurons, glial elements grow in place of dead cells or voids remain.

It is known that the stage of the disease, due to the development of pathomorphological changes in the cells, is characterized by irreversible changes that progress over time and entail neurological complications.

Researchers at the Carolina Institute found that a neurodegenerative disease, Parkinson's disease, can be partially attributed to brain inflammation. Scientists explain this statement by the activation of microglia cells in the brain, which can cause inflammation, leading to the death of neurons. Harvard research ("Neurology") has shown a reduction in the risk (up to 40%) of people with Parkinson's disease by using the anti-inflammatory effect of non-steroidal anti-inflammatory drugs, and their potential for preventing colorectal cancer and treating other conditions such as cancer and cardiovascular diseases.

It is known that at an early stage of Parkinson's disease, antibodies begin to form in the human body to neutralize the amyloid-forming alpha-synuclein protein.

The possibility of the formation of antibodies in the body can be regarded as the result of an inflammatory reaction of autoimmune origin. Autoimmune reactions fulfill a “protective” role, leading to damage or degeneration of vital organs.

The starting point for the start of autoimmune processes can be infectious inflammation. During the period of acute respiratory viral infection, patients often have a violation of the sense of smell.

Hypo- and anosmia can develop after a previous acute respiratory viral infection occurring against the background of hyperthermic syndrome. Thus, patients examined in St. Petersburg Research Institute of ENT, noted a history of acute nasal congestion during the period of acute illness, anosmia, profuse rhinorrhea, headache, weakness, drowsiness, and an increase in body temperature above 38.5 ° C.

It is known that the temperature reaction is primarily provided by IL-1β, which is considered a powerful pyrogen, with a significant increase in which conditions arise that can lead to the denaturation of protein molecules, which invariably leads to cell death - apoptosis.

Today, there are many viruses that, when introduced, release IL-1β, which provides a hyperergic reaction and a cascade of immunological reactions aimed primarily at “protecting” the body in order to displace pathogens. Major tissue damage, or generalization of inflammation, due to the inadequate functioning of local protective mechanisms, leads to the appearance of IL-1 in the circulation and its systemic effect associated with the activation of an acute phase response at the body level and stimulation of the functions of various organs and systems necessary to ensure immunological reactions.

In this regard, the systemic effect of IL-1 affects the following main changes in the regulation of the constancy of the internal environment of the body, which are interrelated and can be defined as: 1) activation of the neuroendocrine system, 2) restructuring of the immunopoiesis and immunostimulation, 3) a change in the synthesis of acute phase proteins in the liver, 4) a change in the number of circulating leukocytes and stimulation of bone marrow hematopoiesis.

An increase in body temperature is one of the first signs of the spread of the inflammatory process. Pyrogenicity is one of the important properties of IL-1, and this function has been considered the main characteristic of the molecule for many years.

IL-1 does not cross the blood-brain barrier, but acts on the neurons of the special zone of the anterior hypothalamus in the region of the thermoregulatory center, inducing a cascade of changes involving the production of other cytokines and, ultimately, prostaglandin E2 synthesis.

In addition to influencing the thermoregulatory center, IL-1 is involved in numerous neurohumoral connections of the pituitary-hypothalamic site. The introduction of IL-1 causes an increase in the synthesis of a number of neurotransmitters, increased levels of ACTH and corticosterone in plasma due to the induction of corticotropin-releasing factor in the hypothalamus, although the direct effect of IL-1 on the adrenal cortex has also been described.

IL-1 has many central effects that lead to a change in some behavioral reactions, to the induction of slow-wave sleep, loss of appetite, and aimed at the complete mobilization of defenses to fight the infection.

The central manifestations of the action of IL-1 may partly explain the emotional and behavioral changes observed during the course of infectious diseases. In vivo, synthesized at the periphery and circulating in the blood, IL-1 does not penetrate the brain.

However, according to V.A. Lesnikov, the experimental introduction of IL-1 directly into the ventricles of the brain causes changes in thermoregulation and indicators of the immune response. Recently, it has been proven that IL-1 can be synthesized in the brain mainly by glial cells, and this reflects the development of an acute phase response in the periphery.

In addition, the expression of functionally active type I-1 receptors has been shown in various brain structures. The synthesis and action of IL-1 in the brain is a special isolated intracerebral regulatory system, since IL-1 does not penetrate the bloodstream into the brain and vice versa. In this case, the transmission of activating and regulatory signals to the periphery to the organs and cells of the immune system occurs through neutral connections and the synthesis of neurotransmitters in the field of peripheral nerve endings.

The pool of IL-1 synthesized in the brain is not directly related to the pool of this cytokine in the periphery, although they depend on each other.

Thus, locally, the cytokines of the IL-1 family are responsible for all successive stages of the development of an adequate response to the introduction of a pathogen, ensuring its localization and removal, and then restoration of the damaged tissue structure, wherever an inflammatory reaction develops, including brain tissue.

In case of failure of local protective reactions, inflammation continues to develop, provoking an increase in the synthesis of cytokines. An inflammatory reaction, accompanied by hyperthermic syndrome in the brain tissue, leads to damage to cellular structures, and the cytokine defense signaling system reverses its reserves against its own body.

Cytokines are regulatory peptides produced by body cells. Cytokines include simple polypeptides, more complex molecules with internal disulfide bonds, and proteins consisting of two or more identical or different subunits, with a molecular weight of 5 to 50 kDa.

Cytokines are endogenous mediators that can be synthesized by almost all nucleated cells of the body, and the genes of some cytokines are expressed in all cells of the body, without exception.

The cytokine system currently includes about 200 individual polypeptide substances. All of them have a number of common biochemical and functional characteristics, among which the following are considered the most important: pleiotropy and interchangeability of biological action, lack of antigenic specificity, signaling by interaction with specific cellular receptors, and the formation of a cytokine network.

In this regard, cytokines are isolated in a new independent system of regulation of body functions, which exists along with nervous and hormonal regulation.

At the same time, cytokines are the most universal system of regulation, since they are able to exhibit biological activity both distantly after secretion by the producer cell (topically and systemically), and upon intercellular contact, being biologically active in the form of a membrane form.

This distinguishes the cytokine system from adhesion molecules that perform narrower functions only with direct contact of cells. At the same time, the cytokine system differs from hormones, which are mainly synthesized by specialized organs and have an effect after entering the circulation system.

The appearance of cytokines in the bloodstream immediately leads to an increase in the synthesis of steroid hormones, and IL-1 and other pro-inflammatory cytokines cause both an increase in the synthesis of releasing factors and stimulation of hormone production by adrenal cortex cells. Steroid hormones, known as one of the most powerful immunosuppressants, block the synthesis of cytokines and do not allow their level to exceed the limit values.

This is an effective negative feedback mechanism for controlling the overproduction of cytokines. Nevertheless, in some cases, the levels of cytokines exceed physiological concentrations. Cytokines in low concentrations are necessary for the proper formation of local inflammation, higher doses cause the development of a systemic inflammatory reaction, but pathologically high concentrations lead to a state of septic shock and death of the body.

Cytokines include interferons, colony-stimulating factors (CSF), chemokines, transforming growth factors; tumor necrosis factor; interleukins with prevailing historically serial numbers and some others. Interleukins include pro- and anti-inflammatory cytokines, growth and differentiation factors of lymphocytes, individual regulatory cytokines.

The name "interleukin" is assigned to the newly discovered mediator if the criteria developed by the nomenclature committee of the International Union of Immunological Societies are met. The criteria are: molecular cloning and gene expression of the studied factor, the presence of a unique nucleotide and its corresponding amino acid sequence, obtaining neutralizing monoclonal antibodies.

In addition, the new molecule must be produced by cells of the immune system (lymphocytes, monocytes or other types of leukocytes), have an important biological function in the regulation of the immune response, as well as additional functions, which is why it cannot be given a functional name.

The pro-inflammatory cytokines currently include IL-1α, IL-1β, IL-2, IL-6, IL-8, TNFα, interferon gamma (IFNg), anti-inflammatory cytokines are the IL-1 receptor antagonist (IL-1RA), IL-4, IL-10. At present, a large number of recombinant analogues of cytokines, including those involved in the regulation of inflammation, have been obtained, in addition, their number is constantly growing.

In clinical immunology, autoimmune diseases are considered one of the most difficult problems. For ten years, Paul Ehrlich’s statement that the normal immune system should not develop an immune response against its own tissues, as this inevitably leads to the death of the body, is confirmed by new studies in the field of immunology.

Today, there are more than 20 theories that explain the causes of autoimmunity.

In recent years, much attention has been paid to the pro-inflammatory cytokines IL-1, IL-2, γ-INF, followed by the inclusion of apoptosis in autoimmune processes. It is known that the activity of all cytokines involved in inflammation reactions is realized by a similar mechanism, therefore, we examined IL-1. This cytokine is multifunctional and performs many different functions, the targets of which are cells of almost all organs and tissues. The main producers of IL-1 are monocytes and macrophages, and many other cells of the human body, in particular keratinocytes, can also produce IL-1.

IL-1 is an inducible protein, the synthesis of which begins in response to the introduction of microorganisms or tissue damage, which is necessary for the development of local inflammation and the implementation of the whole complex of protective reactions called acute phase response.

Allergic conditions (allergic rhinitis, bronchial asthma, allergic conjunctivitis, food allergy, IgE-associated atopic dermatitis) are a genetically determined group of diseases characterized by an increased ability of B lymphocytes to synthesize class E antibodies (IgE) directed against a special group of antigens called allergens. IgE interact with the high affinity membrane Fcε R1 receptors of basophils and mast cells, which leads to degranulation and release of vasoactive amines, primarily histamine, as well as chemokines and pro-inflammatory cytokines, which induce the development of allergic inflammation.

The late phase of allergic inflammation is associated with the migration into the tissue of various types of leukocytes, especially eosinophils, and their synthesis of low molecular weight mediators and cytokines that support the development of allergies.

Excessive activation by proinflammatory cytokines of one of the types of T-helpers, normally in equilibrium, can direct the immune response according to one of the development options. Chronic imbalance in the activation of T-helpers, along with genetic prerequisites, leads to the development of immunopathological conditions associated with manifestations of allergies or autoimmunity.

It has now been proven that functional (responsible for the altered expression and production of the corresponding protein) polymorphism of genes encoding a number of known pro- and anti-inflammatory cytokines that carry small mutational changes (point nucleotide substitutions (SNPs, single nucleotide polymorphism) or tandem repeats of gene parts ( VNTR, variable number tandem repeat)), can lead to an imbalance of the inflammatory and anti-infection immune response.

Allelic variants of the genes of a number of pro- and anti-inflammatory cytokines responsible for the increased production of the proteins encoded by them were identified: IL-1α-nucleotide substitution at (-889), IL-1β (+3953), IL-1β (-511) (Fig. 11), IL-IRA (VNTR), TNFα (-308), IL-6 (-174), IL-4 (-590), IL-10 (-1082), IFNg (+874), IL-2 ( -330) and others, the frequency of occurrence of which in a number of populations in heterozygous form reaches 40-50%, and in homozygous 10-15%.

Thus, depending on the individual set of high- or low-producing variants of these genes, the nature of the inflammatory response may vary between individuals with "polar" combinations: for example, the "pro-inflammatory genotype" - the majority of pro-inflammatory cytokine genes (IL-1α, IL-1β, TNFα , IFNγ, etc.) are highly producing, and anti-inflammatory cytokines (IL-1RA, IL-4, IL-10, etc.) are low-producing; or "anti-inflammatory genotype" - the carriage of normal variants of pro-inflammatory cytokine genes in combination with highly producing variants of anti-inflammatory cytokine genes.

The activity of all proinflammatory cytokines involved in inflammation reactions is practically realized and regulated by a similar mechanism, the effect of functional polymorphism of cytokine genes on the nature of the immune response can be considered using the protein of the IL-1 family as an example, as IL-1 is the main mediator of the development of inflammation and the whole complex of reactions acute phase response.

It was previously noted - IL-4 suppresses the production of the cytokine IL-1, the level of which can exceed normal values and can persist for a long time in the focus of inflammation.

IL-1 is a multifunctional cytokine and performs at least 50 different functions, which can also serve as targets for nerve cells.

In the IL-1 family, it is customary to include IL-1α, IL-1β, IL-18 IL-1 receptors (IL-1Re) and the receptor antagonist of this cytokine (IL-RA). The balance between production, expression and inhibition of protein synthesis of the IL-1 family plays one of the key roles in the development, regulation and outcome of the inflammatory process. The IL-1 gene cluster (430 Kb) is located on the 2ql3 chromosome and contains the genes IL-1α, IL-1β, IL-1Re receptor and IL-1RA, the structure of which is quite conservative.

Some allelic associations of IL-1 family genes are responsible for the altered expression and production of the proteins encoded by them. A number of SNP markers of a highly producing variant of the IL-1β gene were identified, usually inherited jointly (+3953, -511, -3737, -1469, -999). Carrier of polymorphic variant 2 of the IL-IRA gene (VNTR) carrying a series of repeats of 86 bp (IL-1RA * 2) is associated with an increased level of circulating IL-1RA and the level of mRNA expression of this protein during inflammation.

It is known that with the carriage of highly producing gene alleles (IL-1β * 2), the protein encoded by the DNA molecule produces a greater amount of cytokine against the background of developed inflammation. The presence of combinations in the genome (the “+” sign - a variant of the gene is present, the “-” sign is absent) IL-1β (SNP) + / IL-1RA * 2-, IL-1β (SNP) - / IL-1RA * 2 + and IL-1β (SNP) + / IL-1RA * 2 + can have a significant effect on the ratio of expression and production of these proteins and is one of the main causes of dysregulation of the inflammatory response.

According to population studies, the IL-1RA * 2 variant is more often found in association with the normal (low-producing) variant of the IL-1β gene (IL-1β * 1) and is rarely present in conjunction with the high-producing variant, IL-1β * 2 (the marker is one of nucleotide substitutions listed above). The phenomenon of this inheritance is explained by the fact that these variants of genes located close to each other are usually inherited jointly.

In individuals heterozygous for these variants of genes, one of the chromosomes carries the haplotype IL-1β * 1 / IL-1RA * 2, the second - IL-1β * 2 / IL-1RA * 1, resulting in a combination of "1/2" IL -1β + "1/2" IL-1RA. The haplotype IL-1β * 2 / IL-1RA * 2 is found in 1-2% of the population and, most likely, is the result of meiotic recombination.

Currently, there is a transition from diagnosis and mass therapy to diagnosis and individual therapy, which allows to cure a specific patient. The absence of significant prognostic factors for the evidence of the development of pathology does not allow doctors to develop a patient treatment tactics in advance that allows to maximize the clinical manifestations of the disease, possibly genetically programmed.

For many decades, the central nervous system of man was considered privilegedly protected, from immune surveillance, as a powerful blood-brain barrier.

To date, it has been proven that endothelial cells of brain capillaries differ from systemic capillaries, they are rich in mitochondrial cells, have pinocytic vesicles and are in close contact with each other and astrocytes that regulate the permeability of endothelial cells, providing high electrical resistance. The blood-brain barrier is a bi-directional regulatory membrane between the blood and the brain.

The regulatory membrane is able to protect brain cells from adverse effects and selectively skip nutrients. With the development of autoimmune processes, this ability of endothelial cells is impaired. In understanding the immunopathogenesis of demyelinating diseases of the nervous system, the development of experimental models, in particular, experimental allergic encephalomyelitis, has contributed.

In Parkinson’s disease, Lewy bodies, spherical eosinophilic cytoplasmic inclusions, are found in black matter and a pale ball of the brain (Fig. 2).

The presence of eosinophilic cells may indicate eosinophilic inflammation in the brain tissue. In patients with Parkinson's disease, an increase in the level of IL-4 (B-cell stimulating factor) is noted. The function of IL-4 is to switch the synthesis of IgG1 to the synthesis of IgG4 and IgE. IgE is a protein whose increase, as a rule, is noted in allergic conditions, manifested by eosinophilic inflammation.

An increase in the level of IL-4 during the height of Parkinson's disease with a vivid clinical picture, when the degeneration of brain neurons is about 80%, recalls the fact that IL-4 is a pro-inflammatory cytokine that is an antagonist of γ-interferon. IL-4 inhibits the production of acute phase cytokines IL-1, IL-6, IL-8, ejected during the period of inflammation.

Allergic conditions are considered a genetically determined pathology characterized by an increased ability of B lymphocytes to synthesize class E antibodies (IgE) directed against a special group of antigens called allergens.

IgE interacts with high affinity membrane Fc _ε R1 receptors of basophils and mast cells, which leads to degranulation and release of vasoactive amines, primarily histamine, as well as chemokines and pro-inflammatory cytokines, which induce the development of allergic inflammation.

Allergic inflammation is conventionally divided into two main phases, immediate and late. The first can develop within a few seconds and is associated with an allergen-induced IgE-dependent synthesis of histamine and other mediators by tissue mast cells. The late phase of allergic inflammation is associated with the migration into the tissue of various types of leukocytes, especially eosinophils, and their synthesis of low molecular weight mediators and cytokines that support the development of allergies.

This concept confirms the inflammatory and autoimmune theory of the development of Parkinson's disease.

Cytokines have pleiotropic biological effects on various types of cells, mainly by participating in the formation and regulation of the body's defense reactions. Defense at the local level develops by forming a typical inflammatory reaction after the interaction of pathogens with pattern-recognizing receptors (membrane Toll receptors), followed by the synthesis of pro-inflammatory cytokines.

Synthesizing in the focus of inflammation, cytokines act on almost all cells involved in the development of inflammation, including granulocytes, macrophages, fibroblasts, endothelial and epithelial cells, and then on T and B lymphocytes. Within the framework of the immune system, cytokines interconnect non-specific defense reactions and specific immunity, acting in both directions.

An example of cytokine regulation of specific immunity is the differentiation and maintenance of the balance between T-lymphocytes of helper types 1 and 2. In case of failure of the local protective reactions, cytokines enter the circulation, and their effect is manifested at the systemic level, which leads to the development of an acute phase response at the body level. At the same time, cytokines affect almost all organs and systems involved in the regulation of homeostasis.

The action of cytokines on the central nervous system leads to a change in the whole complex of behavioral reactions, the synthesis of most hormones, acute phase proteins in the liver, the expression of genes of growth and differentiation factors, the plasma ion composition changes.

However, none of the changes taking place is random: all of them are either necessary for the direct activation of protective reactions, or are beneficial in terms of switching energy flows for only one task - the fight against the introduced pathogen. Cytokines are the main mediators of anti-infection resistance, including protection against viruses. At the body level, cytokines provide a link between the immune, nervous, endocrine, hematopoietic and other systems and serve to engage them in organizing and regulating a single defense reaction.

Thus, cytokines serve as the organizing system that forms and regulates the whole complex of pathophysiological changes during the introduction of pathogens.

It should also be noted that the regulatory role of cytokines in the body is not limited to the immune response only. It can be divided into 4 main components: regulation of embryogenesis, laying and development of a number of organs, including organs of the immune system; regulation of individual normal physiological functions, for example, regulation of normal hematopoiesis; regulation of protective reactions of the body at the local and systemic level; regulation of regeneration processes to repair damaged tissues.

Establishing causal relationships between the carriage of genetic variants, the predisposition and the nature of the development of Parkinson's disease can provide an opportunity for preventive measures to prevent severe manifestations of the disease, by searching and developing effective methods of treatment.

The individual functioning of the cytokine system can be determined by several factors, including differences in the production of cytokines due to a number of biological features. The search for hereditary foundations that determine a predisposition to the development of inflammatory and infectious diseases is aimed at identifying the genes responsible for controlling immune responses.

The prognosis of the effectiveness of a comprehensive early diagnosis of Parkinson's disease is relevant, and the determination of the immunogenetic characteristics of the patient will allow in the future to develop a reasonable and effective tactics of prevention and treatment.

There is a method of preclinical diagnosis of Parkinson's disease in healthy individuals (see patent RU No. 2318437, AB 5/11, 2008).

In the implementation of this method, a provocative test is carried out, in which case a pharmacological preparation is injected into the blood of the subject with subsequent determination of the reaction of the test organism to its effect, and a reversible inhibitor of catecholamine synthesis α-methyl-p-tyrosine is administered as a pharmacological preparation, the presence / the absence of tremor and / or muscle rigidity, in the presence of which a pathological process is diagnosed in the latent phase of the course.

The method allows to identify the disease in the latent phase of development, and therefore, apply preventive treatment.

The disadvantage of this method is that the latent (early or latent) stage of Parkinson's disease is distinguished by the absence of tremor and muscle stiffness, visible to a specialist neurologist, and when these symptoms appear, a diagnosis is established and therapy is prescribed to stop them. It is worth noting that the clinical manifestations of the diagnosis occur with degeneration from 60 to 80% of the nervous tissue.

There is also a method for predicting the effectiveness of treatment with interleukin-1 (see patent RU No. 2301012, AB 5/01,2007).

When implementing this method, the totality of genotyping data is analyzed according to the signs of allelic polymorphism of the cytokine gene and indicators of the patient’s body temperature in response to the first injection of the drug. If a patient has a cytokine gene homozygous for a high-producing allele and changes in temperature upward, low treatment efficiency is predicted, and if a patient has a cytokine gene homozygous for a low-producing allele and no temperature increase, a high treatment efficiency is predicted.

This method is simple to implement and allows you to make a prediction of the effectiveness of treatment with IL-1 based on the individual susceptibility of the patient to treatment with this drug to eliminate the side effect of the upcoming therapy. It provides a comprehensive assessment of genotyping and clinical symptom data - hyperthermia in patients.

The disadvantage of this method is that it is applicable only to predict the effectiveness of cytokine therapy, but cannot be used for early diagnosis of the disease.

Closest to the technical nature of the claimed solution is a method for determining treatment tactics with a recombinant cytokine that regulates inflammation (see patent RU No. 2271827, A61K 38/20, C12Q 1/68, 2006).

In the implementation of this method, the definition of functional polymorphism of the cytokine gene is used as a prognostic criterion for the degree of effectiveness and side effect of therapy with a recombinant cytokine analogue.

The method allows to predict the effectiveness of treatment with a recombinant cytokine that regulates inflammation, depending on the genetic characteristics of the body, but it is not suitable for identifying the early stages of the disease.

The technical result of the invention is a targeted, comprehensive diagnosis of Parkinson's disease in the latent stage.

To achieve the indicated technical result in a method for diagnosing Parkinson’s disease in patients with impaired sense of smell, including the determination of impaired smell after an acute respiratory viral infection accompanied by hyperthermia, immunodiagnostics, according to the proposal, conduct a complex of studies containing the definition of IL-1β alleles (-511 ) “2/2”, “1/2”, HLA-DRA rs3129882 SNP, increased production of IL-1β, polysomnography data, and, in patients with hypo- or anosmia, carriage of alleles of IL-1β (-511) “ 2/2 "," 1/2 ", HLA-DRA rs3129882 SNP, increased serum cytokine production, a disorder of behavior associated with REM-sleep, diagnose Parkinson's disease.

At an early stage of the development of Parkinson's disease, we established, taking into account the patient's initial complaint about a decrease in olfactory function, a previous viral infection against the background of hyperthermic syndrome, significant changes in the cytokine status. By genotyping, the carriage of highly producing alleles of IL-1β * 2 genes was determined. This was done to identify in a patient an increased ability to produce serum products in response to the introduction of a pathogen (bacteria, viruses, etc.), which subsequently can lead to a cascade of autoimmune reactions that lead to degenerative changes in the nervous tissue that invalidates the person and inevitably leads to to his death.

Based on the patient’s first complaint of a decrease or absence of smell after a previous acute respiratory viral infection accompanied by a significant increase in body temperature (above 38.5 ° C), the patient undergoes a complete rhinological examination confirming the absence of objective reasons for the violation of the smell function. Next, blood sampling is carried out for immunogenetic analyzes in order to identify alleles of the IL-1β (-511) 1/2, 2/2 gene and the HLA-DRA rs3129882 SNP carriage, and the level of serum IL-1β production is also assessed. A neurological examination is performed to identify the symptoms of extrapyramidal insufficiency, followed by polysomnography.

The method is based on the influence of functional polymorphism of cytokine genes and the main histocompatibility complex on the nature of the immune response, maintaining high levels of serum production, as well as provoking an autoimmune process, which subsequently leads to degeneration of nerve tissue.

Primary brain changes are also reflected in the evaluation of polysomnography.

From an analysis of the above known sources of information, it is clear that the classical methods for diagnosing PD today are diverse, but do not fully allow for a reliable diagnosis, as they are based on clinical signs that do not cover the entire spectrum of damage to the nervous system in Parkinson's disease. Some methods make it possible to establish a diagnosis when the number of motor neurons dead is large enough, while others entail overdiagnosis.

Early diagnosis could prevent the destruction of up to 60% of nerve cells in the corresponding areas of the brain, thereby saving a significant number of patients from early disability and death.

The inventive method contains the following research complex:

1. Collection of medical history (transferred ARVI with hyperthermic syndrome).

2. Otorhinolaryngological examination, in order to exclude pathological processes in the olfactory zone, including:

- rhinoscopy, examination of the nasal cavity with the help of video surveillance;

- computed tomographic examination of the nose and paranasal sinuses (figure 3);

- testing of olfactory function, according to the method of Bronstein.

3. Neurological examination to detect extrapyramidal insufficiency, including an assessment of: the motor sphere (muscle tone, strength, reflexes); sensitive sphere (superficial, deep); coordination samples; meningeal signs, autonomic functions.

4. Polysomnography method, including: electroencephalogram (EEG), electromyography (EMG), electrooculography (EOG), electrocardiography (ECG), sleep phase study Rapid eye movement (REM), fast eye movements.

The study is carried out at night using Grass Technologies equipment in a montage with 4 channel EEG in monopolar lead, two EOG channels, chin EMG channel, ECG lead channel, chest and abdominal breathing channels, body position channel, with parallel video monitoring, without an adaptive night. The hypnogram is commented on taking into account the total study time (minutes). Total sleep time (minutes). Sleep Efficiency (%). The ability to maintain sleep (%). Latency to sleep (minutes). Latency to persistent sleep (minutes). Latency to REM sleep (minutes). Assess the architecture of sleep (stage N1) as a percentage of the total sleep time, N2, N3, REM sleep (%).

Over the study period, the number of occurring REM sleep episodes and the number of awakenings with a total duration of minutes are taken into account. EEG activations are recorded with a determination of the relationship with apnea and hypopnea, and a spontaneous nature is also recorded. The index A \ H is recorded. Estimate the level of saturation of arterial blood oxygen (% - saturation), the minimum and maximum. The desaturation index is calculated. Calculate the average heart rate per minute. Measure blood pressure in the evening and blood pressure in the morning (mmHg).

5. HLA typing (Fig. 1) is performed according to Sequence Specific Primers technology, which is based on PCR using allele-specific primers that "capture" the desired HLA DNA regions with subsequent detection by gel electrophoresis.

The first step is to extract DNA from the test blood sample, the DNA is amplified (45 min - 1.5 hours). DNA is dug into the wells of a PCR plate, each of which contains primers of a specific specificity. The number of wells (PCR reactions) is respectively determined by the number of allelic variants at each locus. Amplicons are transferred to the wells of an agarose gel. In those wells where the specificities of the primers coincided with specific regions of DNA, a strip of product appears in the gel. Using the interpretation table or using a program, we determined which HLA alleles correspond to the product band.

6. The immunogenetic method is performed in order to detect the carriage of highly producing alleles of the IL-1β gene (-511). To identify point single nucleotide substitutions (SNPs) in the IL-1β gene (-511), a method for analyzing the length of restriction fragments of the PCR product was used.

At the first stage, a polymerase chain reaction (PCR) is carried out using specific primers (FIGS. 4, 5) specific for a region of genomic DNA containing known SNPs.

The reaction mixture is prepared in a volume of 30 μl: 3 μl of 10-fold buffer; a mixture of dNTP at a concentration of 170 nm; 50 pM of each primer (0.5 μl of a 100 μM solution); 1 unit Taq polymerase; 1-2 μl of DNA; H ₂ O up to 30 μl. DNA amplification modes are shown in Fig.6.

The DNA amplification product is precipitated by adding 90 μl of 96% ethanol and 3 μl of 7.5 M ammonium acetate to 30 μl of the reaction mixture. Then mixed and centrifuged in a microcentrifuge for 15 minutes with an acceleration of 10000g. The supernatant was pipetted, 400 μl of 70% ethanol was added and centrifuged again at 10,000 g for 6 minutes, then the alcohol was removed and the precipitate was dried at 560 ° C and dissolved in 9 μl of distilled water.

To carry out PCR restriction, the product is incubated for three hours with an appropriate restriction enzyme (Fig. 7). The restriction products were separated electrophoretically in a 2% ethidium bromide agarose gel and visualized in UV light on a transilluminator (Fig. 8).

Molecular weight markers with a step of 100 bp were used as a marker of the size of the obtained DNA fragments.

The following abbreviations are used to briefly identify the alleles of the IL-1β (-511) genes: normal, not bearing a detectable mutation, the allele is denoted by the number 1, polymorphic - 2, respectively, the homozygous normal gene is “1/1”, the homozygous highly producing gene is “2 / 2 ", heterozygous -" 1/2 ".

If the patient identifies a 2/2 variant of the cytokine gene, the development of Parkinson's disease is predicted. If the patient reveals the 1/2 variant of the cytokine gene, the average probability of developing Parkinson's disease is predicted. If the patient reveals the 1/1 variant of the gene, a low probability of developing Parkinson's disease is predicted.

Analysis principle: Quantitative determination of IL-1β is based on the construction on the solid phase (96-well plate for enzyme-linked immunosorbent assay) of a complex consisting of: 1) murine monoclonal antibodies that specifically bind IL-1β from solution; 2) IL-1β; 3) rabbit polyclonal antibodies to IL-1β; 4) horseradish peroxidase conjugate with goat antibodies to rabbit immunoglobulins.

The complex is formed by sequentially adding the appropriate reagents to the board, the excess of which after incubation is removed each time by aspiration and washing the board. The amount of bound conjugate that determines the intensity of color development in each well after the addition of a chromogen solution is proportional to the amount of IL-1β in the test sample. The result of the analysis is calculated according to the calibration graph after measuring the optical density.

7. The immunological method is performed to determine the level of serum production of IL-1β. Serum cytokines levels are determined by solid-phase ELISA using polystyrene plates, test systems (IL-1).

First, the first monoclonal antibodies to the corresponding cytokine are sorbed onto the plate in an amount of 50 μl per well at a concentration of 10 μg / ml in 0.1M pH 9.0 sorption carbonate buffer for 1 hour at room temperature on a shaker.

After that, double washing with phosphate buffer 0.05M pH 7.2 with 0.1% detergent NP-40 is carried out. When washing, in each well of the tablet, 100 μl of washing phosphate buffer is added with a 12-channel automatic pipette, after which the introduced buffer is gently decanted and aspirated.

At the end of the washing, a blocking stage is carried out, adding 100 μl to each well of phosphate 0.05 M buffer with 1% BSA, after which a double washing is also carried out as described above.

At the next stage, the studied samples of serums or supernatants are added in the amount of 50 μl per well, performing 2-3 double dilutions in 3 parallels. Dilutions of sera and supernatants are carried out in washing phosphate buffer.

Simultaneously with the samples, a standard cytokine sample in different concentrations is introduced into one of the rows of the tablet. The sample plate is incubated for 1 hour on a shaker at room temperature, or left overnight at + 4 ° C. At the end of the incubation, the samples are washed twice as described above.

Then, a second polyclonal rabbit anti-cytokine antibody corresponding to cytokines is added to the plate in an amount of 50 μl per well at a concentration of 1 μg / ml. Incubation with the second antibodies is carried out for 1 hour under the same conditions as the previous stages.

At the last stage, after the next two-time washing, goat anti-rabbit antibodies labeled with horseradish peroxidase are introduced into the plate to reveal polyclonal rabbit antibodies. Incubation with the last conjugates is carried out for 1 hour under the same conditions, the concentration of these conjugates is selected empirically for each specific cytokine.

At the end of the last stage, a four-fold washing is carried out and then stained in phosphate-citrate buffer 0.1 M pH 5.0 with the dye added orthophenylenediamine at a concentration of 0.5 mg / ml and hydrogen peroxide 0.06% as a substrate.

Staining is carried out in the dark at room temperature for 15-20 minutes until the stained product of the enzymatic reaction appears completely. Stop the reaction by introducing into the wells of an equal volume of 1 ml of HSO. The reaction results are taken into account at a wavelength of 495 nm on a spectrophotometer for the tablet. The concentration of a particular cytokine in the sample is determined by the calibration curve of the ratio of the optical density of the solution in the well and the known concentration of this cytokine as a standard, multiplying by the corresponding dilution of the sample.

And if a patient has a homo- and heterozygous allele of the cytokine agonist gene, a high probability of developing Parkinson's disease is predicted.

On the basis of experimental data, a relationship was found between laboratory parameters, carriage of the cytokine gene IL-1β (-511) “1/2”, “2/2” homozygous for alleles, HLA-DRA rs3129882 SNP carriage, clinical symptoms, the main of which is hypo- or anosmia that developed after a previous acute respiratory viral infection with hyperthermic syndrome, as well as polysomnography, which allows predicting Parkinson's disease in the latent (latent) stage of the disease.

This conclusion is based on genotyping data for the allelic polymorphism of the cytokine gene IL-1β (-511) and the main histocompatibility complex HLA.

This method allows the diagnosis of Parkinson's disease at an early stage of development associated with high production of IL-1β, genetically mediated, carriage of HLA-DRA rs3129882 SNP and IL-1β * 2 (-511) in combination with hypo- and anosmia, supplemented by the detection of motor impairment activity, during sleep, polysomnographic data.

The identification of a homo- or heterozygous, highly-producing variant of the cytokine gene that regulates inflammation can explain the inflammatory trigger theory in the development of a degenerating brain disease, leading inexorably to the death of the patient.

The inventive method will allow you to choose the tactics of treating patients in the early stages of development in order to suppress the inflammatory reaction in the brain by individually selecting a set of therapeutic procedures taking into account the immunogenetic features of the course of extrapyramidal insufficiency.

The method is illustrated by drawings, where;

figure 1 presents the picture of electrophoresis of amplification products of HLA;

figure 2 presents micropreparations, Parkinson's disease with Levy bodies (Edward K. Clatt, MD);

figure 3 presents a computed tomography of the paranasal sinuses of a patient with anosmia;

figure 4 presents a table - a characteristic of the studied IL-1β (-511), IL polymorphism and primer used in their analysis by RFLP-PCR;

figure 5 presents the picture of electrophoresis after RFLP, polymorphic site - IL-1β (-511). Rows: 1 - molecular weight marker for DNA, 100 bp; 2, 3, 5 - heterozygotes with 1/2 alleles; 4, 6 - homozygotes for 1/1 alleles; 7 - homozygote for the 2/2 allele.

figure 6 presents a table - modes of amplification of DNA used for a particular variant of polymorphism;

figure 7 presents the table - the characteristic polymorphic site of the cytokine gene IL-1β (-511);

on Fig presents a photograph of an endoscopic examination of the nasal cavity.

The method is as follows.

At the initial treatment of the patient with a complaint of a decrease or lack of smell, an otorhinological examination is performed to exclude pathology, which may result in a violation of olfactory function. Then, anterior and posterior rhinoscopy is performed, examination of the nasal cavity with the help of video surveillance (Fig. 3), computed tomography of the nose and paranasal sinuses (Fig. 4), testing according to the Bronstein method.

If the patient does not have objective data for the presence of pathology of the nose and paranasal sinuses, and according to the results of olfactory function testing, there is a decrease or lack of sensation of smell, the blood is taken for immunogenetic analysis (IL-1β (-511), level of IL-1β, HLA - typing) and polysomnographic research.

For an accurate forecast, identify:

1. Alleles of the gene IL-1β (-511) "1/2", "2/2";

2. The level of production of IL-1β;

3. Carrier HLA-DRA rs3129882 SNP;

4. The presence of data characteristic of a behavior disorder associated with REM-sleep.

The study includes: taking an anamnesis, damage to the cranial nerves, damage to the motor sphere, damage to the sensitive sphere, damage to the reflex sphere, impaired coordination, cerebellar sphere, identification of meningeal symptoms, determination of cortical functions.

The study is aimed at making a topical diagnosis - the defeat of the extrapyramidal system.

Then a polysomnographic study is performed.

In patients in the early stages of the extrapyramidal system lesion, a disturbance in the sleep process is noted in the form of a decrease in efficiency, increased fragmentation. The latent period of falling asleep is lengthened, the latent period of REM sleep is shortened. The representation of REM sleep increases, while the characteristic REM atony does not appear on the myogram.

During video monitoring, motor activity is recorded in the form of body movements, attempts to stand up, sleeplessness, muscle twitches that coincide with the period of REM sleep.

When detecting in patients with symptoms of hypo- and anosmia, combined with the carrier of the IL-1β (-511) “2/2”, “1/2” and HLA-DRA rs3129882 SNP genes, supplemented by polysomnographic data confirming the manifestation of extrapyramidal disorders, predict the development of Parkinson's disease.

If a patient reveals a combination of the IL-1β (-511) “l / l” gene, a low probability of developing Parkinson's disease is predicted.

However, if a patient has signs of a disease with a predominant lesion of the extrapyramidal system, according to the totality of clinical signs, genotyping and polysomnographic studies, the patient is placed on a dispensary account by a neurologist for the purpose of dynamic observation and treatment, taking into account individual characteristics of the course of neurological pathology.

It is known that IL-1 is the main mediator in the mechanism of development of fever, which is why it is often referred to in literature as endogenous or leukocyte pyrogen. Under normal conditions, it does not cross the blood-brain barrier.

However, in violation of immune homeostasis, IL-1 reaches the preoptic region of the anterior part of the hypothalamus and interacts with neuron receptors of the thermoregulation center.

By activating cyclooxygenase, synthesizing prostaglandins, increasing the intracellular level of cyclic adenosine monophosphate, the activity of the centers of heat production and heat transfer is rearranged with an increase in the generation of heat energy and a decrease in heat release, which causes an increase in body temperature.

An analysis of the presented data shows that this complex of examination of patients provides an opportunity for an early prognosis of a degenerating brain disease and will allow the development of a number of treatment procedures that can slow down the development of Parkinson's disease.

Thus, the carriage of alleles of the IL-1β (-511) gene “2/2”, “1/2” and HLA-DRA rs3129882 SNP in combination with the symptoms of hypo- and anosmia, supplemented by polysomnographic data, indicates the start of pathological autoimmune process in the extrapyramidal system and can be used to diagnose the development of Parkinson's disease.

In patients with hypo- and anosmia that occurred after acute respiratory viral infections against the background of hyperthermia, analysis of the carriage of the alleles IL-1β (-5H) “2/2”, “1/2” and HLA-DRA rs3129882 SNP showed that this complex of polymorphisms may be one of the main reasons for the development of an autoimmune process in brain tissue, which is considered a consequence of the inflammatory response at the systemic level and in the focus of inflammation in patients with Parkinson's disease.

The level of IL-1β in the blood serum activates the functional state of the immune response directly in the focus of inflammation, which is aimed at accelerating the completion of the inflammatory process, however, with a defect in the immune response at the genetic level, a reverse reaction mechanism occurs when the cell of the body becomes the target cell.

After the diagnosis was made in all patients, over time, there was a tendency to increase neurological symptoms, indicating a developmental direction - the progress of Parkinson's disease.

Thus, for patients with PD who, according to the genotyping, are carriers of the polymorphic variant of the IL-1β (-511) gene "2/2", "1/2" and HLA-DRA rs3129882 SNP, supplemented by polysomnographic data confirming the manifestations extrapyramidal disorders, this method is highly effective.

Since the activity of all cytokines involved in the implementation of inflammation is regulated by a similar mechanism, the results obtained on the example of genes of the IL-1 family and HLA genes allow us to state: the presence of 2/2 in the IL-1β (-511) genotype, "1/2" and HLA-DRA rs3129882 SNP is a factor predisposing to the development of Parkinson's disease.

There are currently no drugs or treatments for Parkinson's disease. The possibility of an early prognosis opens up the prospect of finding a pathogenetic treatment that will help prevent the development of the disease and trace the immunological mechanism of the stages of the disabling disease.

Diagnosis of Parkinson's disease in the early stages will allow the use of modern medicines and surgical agents to slow down the development and course of the disease.

Thus, the high medical and social significance of solving the problem is obvious.

The method is illustrated by the following examples.

Example 1

Patient M., 58 years old, complaints of a lack of sensation of smell perception for 6 months after acute respiratory viral infections, accompanied by an increase in body temperature above 38.5 ° C.

Objectively: the mucous membrane is pink, moist. The nasal passages are wide, free, visible, the area of the upper, middle and lower nasal passages without pathological changes. The nasal septum is moderately curved. In the study of olfactory function, according to the method of A.I. Bronstein, I turned off the first pair of cranial nerves. On a series of CT images, airiness of the paranasal sinuses is noted, there are no pathological changes.

According to an immunogenetic study, the following was revealed: carriage of a polymorphic highly producing variant of the IL-1β (-511) “2/2” gene; HLA-DRA rs3129882 SNP; the level of serum production of IL-1β-457 PG / ml

According to a polysomnographic study, there is a disturbance in the sleep process in the form of a decrease in efficiency, increased fragmentation. The latent period of falling asleep is extended and the latent period of REM sleep is shortened. The representation of REM sleep is increased, while the characteristic REM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, attempts to stand up, muscle twitches that coincide with the period of REM sleep. The findings are characteristic of a disorder associated with REM sleep.

According to a neurological examination, dyscirculatory encephalopathy with extrapyramidal insufficiency was established. Parkinson's disease.

Polysomnographic study - after 1 year of observation.

Conclusion: Violation of the sleep process in the form of reduced efficiency, increased fragmentation. The latent period of falling asleep is extended and the latent period of REM sleep is shortened. The representation of REM sleep is increased, while the characteristic REM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, attempts to stand up, muscle twitches that coincide with the period of REM sleep.

The findings are characteristic of a disorder associated with REM sleep. Compared with the previous study, there is a negative dynamics in the form of an increase in motor activity.

Example 2

Patient A., 62 years old, complaints about the lack of sensation of smell, he considers himself sick for about 7 months, the decrease in smell was gradual. The sense of smell has not completely disappeared, but the patient notes a perversion of familiar smells.

Objectively: the mucous membrane is pink, moist. The nasal passages are wide free, the zone of the middle and lower nasal passages without pathological changes. The nasal septum is moderately curved. In the study of olfactory function according to the method of A.I. Bronstein, the olfactory function was turned off. On a series of CT images, airiness of the paranasal sinuses is noted, there are no pathological changes.

According to an immunogenetic study, the following was revealed: carriage of a polymorphic highly producing variant of the IL-1β (-511) “2/2” gene; HLA-DRA rs3129882 SNP; the level of serum production of IL-1β-349 PG / ml

Polysomnographic study: disturbance of the sleep process in the form of reduced efficiency, increased fragmentation. Mild obstructive sleep apnea syndrome. The latent period of REM sleep is shortened. The representation of REM sleep is increased, while the characteristic REM atony does not appear on the myogram. During video monitoring, locomotor activity is recorded in the form of body movements, turns, attempts to stand up, sleeplessness, muscle twitches that coincide with the period of REM sleep.

The findings are characteristic of a disorder associated with REM sleep.

According to a comprehensive examination, discirculatory encephalopathy with extrapyramidal insufficiency was established. Parkinson's disease.

Polysomnographic study - after 1 year of observation.

Conclusion: Violation of the sleep process in the form of reduced efficiency, increased fragmentation. Moderate Obstructive Sleep Apnea Syndrome The latent period of REM sleep compared with the previous study is significantly shortened. The representation of REM sleep is increased, while the characteristic REM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, turns, congestion, muscle twitches coinciding with the period of REM sleep.

The data obtained are characteristic of behavioral disorders associated with REM sleep, there is a negative dynamics in the form of shortening the latent period of REM sleep, aggravation of obstructive sleep apnea compared with the previous study.

Example 3

Patient I., 57 years old, complained of a lack of sensation of smell, within 4 months after an acute respiratory viral infection, accompanied by an increase in body temperature above 38.5 ° C, profuse rhinorrhea, difficulty in nasal breathing.

Objectively: the mucous membrane of the nasal cavity is pink, moist. The nasal passages are wide, free, visible, the area of the upper, middle and lower nasal passages without pathological changes. Nasal septum in the midline. In the study of olfactory function, according to the method of A.I. Bronstein revealed, the shutdown of the first pair of cranial nerves. On a series of CT images, pathological changes were not detected.

According to an immunogenetic study, the following was revealed: carriage of a polymorphic heterozygous variant of the IL-1β (-511) gene "l / 2"; HLA-DRA rs3129882 SNP; the level of serum production of IL-1β-387 PG / ml

Polysomnographic study: disturbance of the sleep process in the form of reduced efficiency, increased fragmentation. Mild obstructive sleep apnea syndrome. The latent period of REM sleep is shortened. The representation of REM sleep is increased, while the characteristic KEM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, congestion, muscle twitching, which coincides with the period of REM sleep.

The findings are characteristic of a disorder associated with REM sleep.

According to a neurological examination, dyscirculatory encephalopathy with extrapyramidal insufficiency was established. Parkinson's disease.

Polysomnographic study after 1 year of observation: disturbance of the sleep process in the form of reduced efficiency, increased fragmentation. Mild obstructive sleep apnea syndrome. The latent period of REM sleep is shortened. The representation of REM sleep is increased, while the characteristic REM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, frequent turning over, standing up, holding up, muscular twitching, which coincides with the period of REM sleep.

The data obtained are characteristic of behavioral disorders associated with REM-sleep, negative dynamics compared with the previous study.

Example 4

Patient A., 60 years old, complaints of lack of sensation of smell, difficulty in nasal breathing, frequent acute respiratory infections, accompanied by fever not exceeding 37.3 ° C. He considers himself sick for about 12 months.

Objectively: the mucous membrane is pink, moist, swollen. The nasal passages are narrowed, the area of the upper, middle nasal passages is not visualized. The lower parts of the nasal cavity, after anemia, are passable, there is no free pathological discharge. The nasal septum is curved more in the upper-middle section. In the study of olfactory function, according to the method of A.I. Bronstein, anosmia was revealed. A series of CT scans showed parietal sinus parietal edema, more pronounced in the cells of the ethmoid labyrinth. Curvature of the nasal septum.

According to an immunogenetic study, the following was revealed: carriage of a polymorphic low-producing variant of the IL-1β (-511) gene "1/1"; HLA-DQB1 * 03 alleles of the HLAII class, HLA-B * 12 alleles of the HLA-B locus; elevated serum production of IL-1β-482 pg / ml.

Polysomnographic study: Changing the sleep process in the form of increased fragmentation, shortening the latent period of REM sleep and increasing its percentage representation. The indices of respiratory disorders and periodic movements of the limbs are normal. During video monitoring, pathological motor activity was not registered.

According to a neurological examination, pathological changes were not detected.

Polysomnographic study - after 1 year of observation.

Conclusion: During video monitoring, pathological motor activity was not registered. Mild obstructive sleep apnea syndrome.

According to an allergological examination, the patient is diagnosed with chronic persistent allergic rhinitis. After treatment courses, olfactory function and nasal breathing have been restored.

Example 5

Patient M., 55 years old, complaints of a lack of sensation of smell, headache in the forehead, fever up to 38.5 ° C, arterial hypertension (190/80), considers himself to be sick after ARVI.

Objectively: the mucous membrane is pink, moist. The nasal passages are wide, free, visible, the area of the upper, middle and lower nasal passages without pathological changes. Nasal septum in the midline. In the study of olfactory function, according to the method of A.I. Bronstein, anosmia was revealed. There are no pathological changes in the CT scan series.

According to the immunogenetic study revealed: carriage of a heterozygous variant of the gene IL-1β (-511) "1/2"; HLA-DQB1 * 02 alleles of the HLAII class, HLA-B * 27 alleles of the HLA-B locus; the level of serum production of IL-1β-528 PG / ml

Polysomnographic study: Changing the sleep process in the form of increased fragmentation, shortening the latent period of REM sleep and increasing its percentage representation. The indices of respiratory disorders and periodic movements of the limbs are normal. During video monitoring, pathological motor activity was not registered.

Based on an objective neurological examination, pathological changes in the central nervous system with the involvement of the extrapyramidal and cerebellar zones were revealed. An additional MRI examination was prescribed, on which foci of changes in the intensity of the MR signal, vascular genesis, and angioma of the right temporal region are noted.

Diagnosis: Hypertension III. Condition after repeated transient ischemic attacks.

Polysomnographic study - after 1 year of observation.

Conclusion: Violation of the sleep process in the form of reduced efficiency, increased fragmentation. The latent period of falling asleep is extended and the latent period of REM sleep is shortened.

The findings are not representative of REM sleep disorder. Compared with the previous study, negative dynamics in the form of an increase in motor activity is not observed.

Example 6

Patient S., 16 years old, complaints of lack of sensation of smell, tingling and “goose bumps” in the arms and legs, bouts of lightheadedness, periodic headache. The patient considers himself sick for 5 months, after suffering an acute respiratory viral infection (temperature above 38.5 ° C).

Objectively: the mucous membrane is pink, moist. The nasal passages are wide, free, visible in full, the area of the upper, middle and lower nasal passages without pathological changes. The nasal septum is moderately curved. In the study of olfactory function, according to the method of A.I. Bronstein, revealed - hypoosmia. On a series of CT images, pathological changes in the nasal cavity and paranasal sinuses were not detected.

According to an immunogenetic study, the patient is a carrier of the IL-1β (-511) “2/2” gene homozygous for a highly producing variant; haplotype consisting of HLAII alleles of class HLA-DRB1 * 1501, DQA1 * 0102, DQB1 * 0602 (a combination is characteristic of multiple sclerosis). The level of serum production of IL-1β-217 PG / ml

Polysomnographic study: Changing the sleep process in the form of increased fragmentation, shortening the latent period of REM sleep and increasing its percentage representation. The characteristic REM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, muscle twitches, which coincide with the period of REM sleep.

The findings are characteristic of a disorder associated with REM sleep.

Based on an objective neurological examination, pathological reflexes were identified. Given the totality of the survey data and the patient's age, an additional MRI scan is prescribed.

According to brain MRI, it was found that in the white matter of the cerebral hemispheres, in the corpus callosum and in a single ^1/2 _{of the} bridge, multiple foci of 0.5 to 2 cm in size are defined, irregularly oblong and round in shape (some with a tendency to merge) with phenomena of moderate perifocal edema of the substance of the brain. MRI picture of a demyelinating disease of the brain.

Diagnosis. Demyelinating disease of the central nervous system. Multiple sclerosis.

Example 7

Patient G., 49 years old, complained of a lack of sensation of smell, for 12 months, after suffering an acute respiratory viral infection, accompanied by an increase in body temperature above 38.5 ° C.

Objectively: the mucous membrane of the nasal cavity is pink, moist. The nasal passages are wide, free, visible, the area of the upper, middle and lower nasal passages without pathological changes. Nasal septum in the midline. In the study of olfactory function, according to the method of A.I. Bronstein revealed anosmia. On a series of CT images, there are no pathological changes in the olfactory zone. The paranasal sinuses are pneumatized.

According to the immunogenetic study, the following was revealed: carriage of a polymorphic heterozygous variant of the IL-1β (-511) “1/2” gene; HLA-DRA rs3129882 SNP; the level of serum production of IL-1β-320 PG / ml

Polysomnographic study: disturbance of the sleep process in the form of reduced efficiency, increased fragmentation. Moderate Obstructive Sleep Apnea Syndrome The latent period of REM sleep is shortened. The representation of REM sleep is increased, while the characteristic REM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, muscle twitches, which coincide with the period of REM sleep.

The findings are characteristic of a disorder associated with REM sleep.

According to a neurological examination, dyscirculatory encephalopathy with extrapyramidal insufficiency was established. Parkinson's disease.

Polysomnographic study after 1 year of observation: disturbance of the sleep process in the form of reduced efficiency, increased fragmentation. Moderate Obstructive Sleep Apnea Syndrome The latent period of REM sleep is shortened. The representation of REM sleep is increased, while the characteristic REM atony does not appear on the myogram. During video monitoring, motor activity is recorded in the form of body movements, muscle twitches that coincide with the period of REM sleep, speaking, frequent turns with a tendency to rise to a vertical position.

The data obtained are characteristic of behavioral disorders associated with REM-sleep, negative dynamics compared with the previous study.

These studies were conducted on the basis of:

- FSBI "St. Petersburg Research Institute of Ear, Throat, Nose and Speech of the Ministry of Health and Social Development of Russia";

- FSUE "GosNII OCHB" FMBA of Russia;

- St. Petersburg State Institution “City Blood Transfusion Station”;

- FGU "St. Petersburg Research Institute of Psycho-Neurological Institute. V.M. Bekhterev ".

Claims (1)

A method for the diagnosis of Parkinson’s disease in patients with impaired sense of smell, including the determination of impaired olfactory function after an acute respiratory viral infection accompanied by hyperthermia, immunodiagnostics, characterized in that a complex of studies containing the determination of alleles of IL-1β (-511) "2/2 ”,“ 1/2 ”, HLA-DRA rs3129882 SNP, increased production of IL-1β, polysomnography data, and when detecting in patients with hypo- or anosmia carriage of alleles of IL-1β (-511)“ 2/2 ”,“ 1 / 2 ", HLA-DRA rs3129882 SNP, increased serum production and cytokine, a disorder associated with REM sleep, diagnose Parkinson's disease.

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