Motor neuron disease is a progressive neurological disease that destroys motor neurons, the cells that control a person's muscle activity such as walking, breathing and swallowing. Typically, signals from nerve cells in the brain (called upper motor neurons) are transmitted to and from nerve cells in the brain stem and spinal cord (called lower motor neurons) to specific muscles. Upper neurons direct lower motor neurons to perform movements such as walking or chewing. Lower motor neurons control movement in the arms, legs, torso, face, throat, and tongue. Dorsal motor neurons are also called anterior horn cells. Upper motor neurons are also called corticospanic neurons.
When disruptions occur in the transmission of signals between the lower motor neurons and a particular muscle, the muscle does not work properly; the muscles gradually weaken, and uncontrollable twitching (so-called fasciculations) may develop. When signal transmission between upper motor neurons and lower motor neurons is disrupted, limb muscles develop spasticity (stiffness), movements become slow and tense, and tendon reflexes in the knee and ankle joints become overactive. Over time, the ability to control voluntary movements may be lost.
Forms of motor neuron disease
Motor neuron diseases are classified according to whether they are inherited or sporadic, and whether the pathology is upper motor neuron or lower motor neuron dependent.
In adults, the most common form of the disease is amyotrophic lateral sclerosis (ALS), which affects both upper and lower motor neurons. The disease has hereditary and sporadic forms and can affect the arms, legs or facial muscles.
Primary lateral sclerosis is an upper motor neuron disease, whereas progressive muscular atrophy affects only the lower motor neurons in the spinal cord.
In progressive bulbar palsy, the lowest motor neurons in the brainstem are most affected, causing symptoms such as slurred speech and difficulty chewing and swallowing.
Symptoms of motor neuron diseases
Below is a brief description of the symptoms of some of the most common forms of motor neurone disease.
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease or classical motor neuron disease, is a progressive, ultimately fatal disease that disrupts signaling in all muscles of the body. Many doctors use the terms motor neuron disease and ALS interchangeably. The disease is caused by disorders of both upper and lower motor neurons. The first symptoms are usually noticed in the arms and legs or in the muscles responsible for swallowing. About 75 percent of people with classic ALS develop weakness of the bulbar muscles (the muscles that control speech, swallowing and chewing). Muscle weakness and atrophy occur on both sides of the body. Patients lose strength and the ability to move their arms and legs and hold their body upright. Other symptoms include muscle spasticity, spasms, and muscle cramps. Speech may become slurred or guttural. When the muscles of the diaphragm and chest wall do not function properly, patients lose the ability to breathe without mechanical support. Although the disease generally does not impair a person's intellectual abilities or personality, some recent scientific research suggests that some people with ALS may develop cognitive (mental) impairment. Most people with amyotrophic lateral sclerosis die from respiratory failure, usually within 3 to 5 years of the onset of symptoms. However, about 10 percent of patients survive for 10 years or more.
Progressive bulbar palsy , also called progressive bulbar atrophy, affects the lower motor neurons responsible for activities such as swallowing, speaking, chewing, and others. Symptoms include weakness of the glossopharyngeal, jaw and facial muscles, progressive loss of speech function, and atrophy of the tongue muscles. Limb weakness in the disease with signs of motor neuron damage is almost always obvious, but less noticeable. People are at increased risk of choking and aspiration pneumonia caused by the passage of fluids and food through the lower respiratory tract and lungs. Affected individuals have emotional outbursts of laughing or crying (called emotional lability). Stroke and myasthenia gravis may have certain symptoms similar to those of progressive bulbar palsy and should be excluded when diagnosing this disease. In about 25 percent of people with ALS, early symptoms begin with associated bulbar abnormalities. Many clinicians believe that progressive bulbar palsy by itself, without signs of pathology in the extremities (arms or legs), is extremely rare.
Pseudobulbar palsy , which has many symptoms similar to progressive bulbar palsy, is characterized by degeneration of the upper motor neurons that transmit signals to the lower motor neurons in the brain stem. Patients develop progressive loss of the ability to speak, chew, and swallow, as well as progressive weakness of the facial muscles. Patients may develop voice disturbances and an increased gag reflex. The tongue may become immobile and lose the ability to protrude from the mouth.
Primary lateral sclerosis (PLS) damages the upper motor neurons of the arms, legs, and face. This occurs when specific nerve cells in the motor areas of the cerebral cortex (the thin layer of cells covering the brain that is responsible for most high-level brain functions) gradually degenerate, causing movements to be slow. The disease often affects the legs first, then the torso, arms, and finally the bulbar muscles. Speech may become slow and difficult. When nerve cells are damaged, leg and arm movements become clumsy, slow and weak, and spasticity occurs, resulting in the inability to walk or perform tasks that require fine hand coordination. Balance problems can lead to falls. Speech may become slow and slurred. Patients typically experience pseudobulbar affect and an overactive response. Primary lateral sclerosis is more common in men than women, and the onset of the disease usually occurs between 40 and 60 years of age. The cause of the disease is unknown. Symptoms progress gradually over many years, resulting in progressive stiffness (spasticity) and clumsiness in the affected muscles. PLS is sometimes considered a form of amyotrophic lateral sclerosis, but the main difference is the sparing of lower motor neurons, a slow rate of disease progression, and a normal life expectancy. Primary lateral sclerosis may be mistaken for spastic paraplegia, an inherited upper motor neuron disorder that causes spasms in the legs and usually begins in adolescence. Most neurologists follow the clinical course of the affected person for at least 3-4 years before making a diagnosis. This disease is not fatal, but can affect quality of life.
Progressive muscular atrophy is characterized by slow but progressive degeneration of exclusively lower motor neurons. The disease largely affects men, with onset earlier than other motor neuron diseases. Weakness usually begins in the arms and then spreads to the lower body, where it can be more severe. Other symptoms may include muscle wasting, clumsy arm movements, and muscle cramps. The muscles responsible for breathing may be damaged. Exposure to cold may worsen symptoms. The disease develops together with ALS in many cases.
Spinal muscular atrophy (SMA) is an inherited disease affecting the lower motor neurons. This is an autosomal recessive disease caused by disturbances in the SMN1 gene (the gene responsible for the production of a protein that is important for the functioning of motor neurons (SMN protein)). In SMA, insufficient levels of SMN protein lead to degeneration of lower motor neurons, causing weakness and wasting of skeletal muscles. Weakness is often more severe in the muscles of the arms and legs, as well as the muscles of the trunk. Spinal muscular atrophy in children is divided into three types based on age of onset, severity, and progression of symptoms. All three types are caused by defects in the SMN1 gene.
Post-polio syndrome (PPS) is a condition that can affect polio survivors, which can occur for decades after they have recovered from polio. Poliomyelitis is an acute viral disease that destroys motor neurons. Many people affected by the disease early in life recover, only to experience new symptoms many decades later. After acute polio, the surviving motor neurons are responsible for more of the muscles they control. Post-polio syndrome and post-polio muscle atrophy are thought to occur when surviving motor neurons are lost through aging or injury/disease. Many scientists believe that SPP is a hidden symptom of muscle weakness previously affected by polio, rather than a new motor neuron disease. Symptoms include fatigue, slowly progressive muscle weakness, muscle atrophy, cold intolerance, and muscle and joint pain. These symptoms most often occur among the muscle groups affected by the initial disease and may consist of problems breathing, swallowing, or sleeping. Other symptoms of SSP may be caused by skeletal deformities, such as long-standing scoliosis, which have led to chronic changes in the biomechanics of the joints and spine. Symptoms are more common in older people and those most affected by earlier illness. Some people have only minor symptoms, while others develop muscle wasting, which can be misdiagnosed as ALS. SSP usually does not threaten the patient’s life. According to medical statistics, 25 to 50 percent of those who have had paralytic poliomyelitis usually develop post-polio syndrome.
Different types of motor neuron disease
Depending on the severity of damage to neurons in the brain and spinal cord, several variants of MND are distinguished. Of course, most of the manifestations coincide, because there is much in common between these types of illness, but as the disease develops, the difference becomes more noticeable.
We'll be talking about life expectancy here, so you may not want to read any further.
Amyotrophic lateral sclerosis (ALS)
This is the most common form of the disease, when motor neurons of both the brain and spinal cord are involved in the pathological process.
ALS is characterized by weakness and a feeling of extreme fatigue in the limbs. Some people experience weakness in their legs when walking and such weakness in their arms that they are unable to hold things and drop them. The average life expectancy is two to five years from the onset of symptoms.
Progressive Bulbar Palsy (PBP)
The term is used mainly in foreign literature. The main difference between PPD and other types of motor neuron disease is the rapidly increasing impairment of speech and swallowing. Life expectancy ranges between six months and three years from the onset of symptoms.
Primary lateral sclerosis (PLS)
A rare form of MND that affects only the motor neurons of the brain, resulting primarily in weakness in the legs, although some sufferers have clumsiness in the arms or problems speaking. PLS does not shorten life expectancy, but there is a possibility that at a certain stage of the disease damage to the motor neurons of the spinal cord will occur, in which case the patient will be diagnosed with ALS.
Find out more about PLS
Progressive muscular atrophy (PMA)
This is a rare type of MND that primarily damages the motor neurons in the spinal cord. The disease in most cases begins with weakness or clumsiness in the hands. Most people live with this type of MND for more than five years.
Find out more about PMA
Here are the most common symptoms and characteristics of the different types of MND. However, it must be remembered that with the same type of motor neuron disease, symptoms may manifest differently in different people, and the prognosis may also differ.
In the case of motor neuron disease, it is generally very difficult to talk about the prognosis. It's rare, but there are cases when people live for decades. The most famous person in the world who has lived with ALS for over 50 years is Professor Stephen Hawking. At the same time, it happens that someone leaves just a few months after the onset of the disease. However, it can be said that the average life expectancy is between two and five years from the onset of symptoms. About 10% of people with MND will live for about 10 years.
Find out more in the article “Types of ALS”
Diagnosis of motor neuron disease
There are no specific tests to diagnose most motor neuron diseases, although genetic testing for SMA genes currently exists. Symptoms may vary among patients and in the early stages of the disease may be similar to those of other diseases, making diagnosis difficult. The physical examination is followed by a thorough neurological examination. Neurological tests will evaluate motor and sensory skills, nervous system functioning, hearing and speech, vision, coordination and balance, mental status, and changes in mood or behavior.
Tests to rule out other diseases or measure the extent of muscle damage may include the following:
Electromyography (EMG) is used to diagnose lower motor neuron disorders, as well as muscle and peripheral nerve disorders. In an EMG, a doctor inserts a thin needle-shaped electrode attached to a recording instrument into the muscle to evaluate electrical activity during voluntary contraction and at rest. Electrical activity in the muscle is caused by lower motor neurons. When motor neurons are lost, characteristic abnormal electrical signals occur in the muscle. Testing usually takes about an hour or more, depending on the number of muscles and nerves being tested.
EMG is usually performed in combination with nerve conduction velocity testing. Nerve conduction studies measure the speed at which impulses are transmitted in nerves from small electrodes attached to the skin, as well as their strength. A small pulse of electricity (similar to a shock from static electricity) stimulates the nerve that controls a specific muscle. The second set of electrodes transmits a response electrical signal to the recording device. Nerve conduction studies help differentiate lower motor neuron disease from peripheral neuropathy and can detect abnormalities in sensory nerves.
Laboratory tests of blood, urine, and other substances can help rule out muscle diseases and other disorders that may have symptoms similar to those of motor neurone disease. For example, analysis of the cerebrospinal fluid, which surrounds the brain and spinal cord, can detect infections or inflammation that can also cause muscle stiffness. Blood tests may be ordered to measure levels of the protein creatine kinase (necessary for chemical reactions that produce energy for muscle contractions); high levels allow the diagnosis of muscle diseases such as muscular dystrophy.
Magnetic resonance imaging (MRI) uses a powerful magnetic field to produce detailed images of tissue, organs, bones, nerves and other structures of the body. MRI is often used to rule out diseases that affect the head, neck and spinal cord. MRI images can help diagnose brain and spinal cord tumors, eye diseases, inflammation, infection and vascular disorders that can lead to stroke. MRI can also detect and monitor inflammatory diseases such as multiple sclerosis. Magnetic resonance spectroscopy is a type of MRI scan that measures levels of chemicals in the brain and can be used to assess the integrity of upper motor neurons.
A biopsy of muscles or nerves can confirm the presence of neurological disorders, in particular impaired nerve regeneration. A small sample of muscle or nerve tissue is taken under local anesthetic and examined under a microscope. The sample can be removed surgically through an incision in the skin or by biopsy, in which a thin, hollow needle is inserted through the skin into the muscle. A small amount of muscle tissue remains in the hollow needle when it is removed from the body. Although this test can provide valuable information about the extent of damage, it is an invasive procedure and many experts believe that a biopsy is not always necessary for diagnosis.
Transcranial magnetic stimulation was first developed as a diagnostic tool to study areas of the brain associated with motor activity. It is also used as a treatment for certain diseases. This non-invasive procedure creates a magnetic pulse inside the brain that causes movement in an area of the body. Electrodes attached to various areas of the body collect and record electrical activity in the muscles. Measures of evoked activity can diagnose motor neuron dysfunction in motor neuron disease or monitor disease progression.
In recent years, due to the increase in the elderly population in developed countries, there has been a steady increase in neurodegenerative diseases, which include Parkinson’s disease (PD) [16, 18, 36]. The prevalence of PD ranges from 100 to 300 people per 100,000 population [54]. In the age group over 65 years, the prevalence is characterized by higher rates - from 1280 to 1500 per 100,000 population [40].
Despite the disease being sufficiently studied, its diagnosis is often delayed. One of the reasons for late diagnosis is late access to a doctor. An analysis of the appeal of patients with PD in one of the districts of Moscow showed that the majority of patients first sought medical help during a period when there were already quite pronounced manifestations of the disease: 67% had stage 2-2.5 of the disease with bilateral symptoms; 5% were at stage 3 and only 28% had stage 1 PD [5]. According to a study conducted in the USA, 25% of patients were not diagnosed with PD within 2 years from the onset of the first symptoms, while 46% of them consulted a doctor within 6 months after the development of clinical manifestations [121]. The second most important factor in late diagnosis is the imperfection of diagnostic criteria.
Currently, the diagnosis of PD is based solely on the clinical picture of the disease. To make a diagnosis of PD, the criteria of the PD Society of Great Britain are used [73], which include the diagnosis of parkinsonism syndrome, as well as criteria excluding and confirming PD. However, their use results in up to 24% of incorrect diagnoses of PD [74]. Therefore, the question arises of searching for additional criteria (biochemical, neuroimaging, neurophysiological, genetic) that can increase the accuracy of diagnosis.
Functional neuroimaging methods
Since PD involves the death of neurons in a certain structure—the substantia nigra—neuroimaging methods are reasonably considered as the only additional methods that can intravitally reveal the presence of a pathological process characteristic of PD. Such methods include positron emission tomography (PET), single-photon emission computed tomography (SPECT), proton magnetic resonance spectroscopy ((1H)-MRS).
Using PET with [18F]-fluorodopa, it is possible to label presynaptic dopaminergic terminals, the number of which progressively decreases in PD [52]. PD is characterized by a decrease in the uptake of [18F]-flurodopa by putamen neurons on the side opposite to motor symptoms. Similar changes are noted on the other side, but to a lesser extent, reflecting the asymmetry of the neurodegenerative process [50, 90]. The rate of accumulation of [18F]-fluorodopa in the striatum reflects the process of transport of fluorodopa into striatal vesicles and its subsequent decarboxylation [91]. The criterion for PD is a decrease in the uptake of this radioligand by 30% or more [52]. When examining twins, one of whom suffered from PD, a decrease in the uptake of labeled fluorodopa in the striatum was found in 44% of clinically healthy monozygotic and 11% of dizygotic twins [82, 97]. When examining healthy relatives of patients with PD, cases of asymptomatic disease were identified in 7 families. The PET prediction index showed the probability of clinical debut of PD in the 4th-7th decade of life in 34% of those examined. After just 1 year, this prediction was confirmed in 36% of cases [50].
The use of PET has made it possible to calculate the rate of dopaminergic neuron loss per year. This amount, according to various authors, ranges from 2 to 9% annually [90], and accordingly the calculated duration of the preclinical stage of PD is 6.0±3.0 years [51, 52].
The state of presynaptic structures can be assessed using other radiopharmacological drugs, for example [11C]-dihydrotetrabenazine. This radioligand allows the labeling of vesicular monoamine transporters [80]. A more accessible technique is PET with F18-deoxyglucose, but its information content is low. The expected reduction in the local rate of glucose utilization in the striatum was not detected. In patients in the initial stages of PD, small focal minor hypometabolism is observed in various structures of the cerebral cortex of a mosaic nature or the absence of pathological changes in metabolism [18].
Performing SPECT with tropane-based drugs ([123I]-β-CIT, [123I]-FP-CIT or [11C]-CFT allows us to determine the amount of dopamine transporter in the synaptic cleft. These radioligands bind to the membrane dopamine transporter in the terminals of nigrostriatal neurons, providing dopamine reuptake.47 PD is characterized by an asymmetric decrease in putamen uptake.104 Binding to the membrane dopamine transporter is a more sensitive marker of early disease, with a greater decrease in uptake early in the disease compared to dihydrotetrabenazine and fluorodopa.111. The less pronounced reduction in early [18F]-fluorodopa uptake may reflect a compensatory increase in decarboxylase activity, but when this compensation becomes insufficient, symptoms appear [84].
The state of dopamine receptors can be assessed by performing PET or SPECT with the dopamine D2 receptor ligand [11C]-raclopride [89]. It has been established [99] that in the initial stages of the disease there is an increase in the density of D2 receptors (the density of postsynaptic D1 receptors does not change). It is believed that such shifts reflect compensation mechanisms under conditions of dopamine deficiency. At later stages, the density of D1 receptors decreases to a greater extent, with relative preservation of D2 receptors. These changes occur in the striatum contralateral to the side of symptoms [115].
The (1H)-MRS method allows you to assess metabolism in almost any area of the brain. According to I.V. Litvinenko [18], in PD, primarily in the projection of the compact part of the substantia nigra, a decrease in the level of N-acetylaspartate (NAA) and an increase in the concentration of choline (Cho) are detected, which leads to a significant decrease in the NAA/Cho ratio. In patients in the early stages of PD (stages I-II according to the Hoehn and Yahr scale), these metabolic changes were the only changes according to (1H)-MRS. There were no changes in the projection of the putamen and globus pallidus in the initial stages of PD.
Despite the high information content of functional neuroimaging methods, they, unfortunately, cannot be used in practical medicine due to technologically complex equipment[], which can only be available to large medical centers. Therefore, all over the world these studies are used primarily for scientific purposes.
Structural neuroimaging methods
In this case, we are talking about X-ray computed tomography (CT) and magnetic resonance computed tomography (MRI). It should be recognized that these methods are not very informative in terms of confirming the diagnosis of PD, but may be important for excluding secondary parkinsonism caused by traumatic brain injury, tumor formations, vascular lesions, etc. [24].
The main structural changes in patients with PD are cerebral atrophy in the form of widening of the cortical grooves and the ventricular system of the brain. The severity of atrophy increases in parallel with the increase in severity and duration of the disease [27, 37, 110]. Thus, at stages I-III of the disease, cerebral atrophy is detected in 23.5%, at stages IV-V - in 100% of cases [2]. The severity of the atrophic process in the akinetic-rigid form of PD is higher than in the trembling form [36].
Attempts to use a morphometric assessment of the width of the zone corresponding to the compact part of the substantia nigra as a diagnostic criterion for PD were unsuccessful - there is an “overlap” in this indicator between patients with PD and the control group [17]. According to F. Lallement et al. [83], MRI in PD may show bilateral decreased signal intensity in the posterior putamen. However, this sign is nonspecific and can be detected in other neurodegenerative diseases [83].
Biochemical markers of PD
A decrease in the activity of mitochondrial complex I, which is detected not only in the substantia nigra, but also in platelets [64] and skeletal muscle cells [96], can act as a biochemical marker. Attempts are being made to determine the level of tyrosine hydroxylase, dopamine and dopamine receptors in peripheral blood lymphocytes, the number of which may decrease even during the initial manifestations of PD [55, 56].
In recent years, increased attention has been paid to the mechanisms of oxidative stress in the pathogenesis of PD. An increase in the activity of the enzyme superoxide dismutase in erythrocytes, which is a natural antioxidant, is detected as a marker of oxidative stress in peripheral blood [118]. According to other studies, the content of 8-hydroxy-2-deoxyguanosine, which is one of the products of oxidative DNA damage, increases in blood serum and urine [79].
In PD, increased levels of glycine, glutamate and aspartate in the blood plasma have been shown, which is explained by excitotoxicity mechanisms involved in the process of neuronal degeneration [76]. A decrease in the level of glutamate (including in the early stages), aspartate, and GABA in the cerebrospinal fluid was also detected [63, 114]. PD is considered to be characterized by a decrease in isoleucine, alanine, and lysine in the cerebrospinal fluid and a moderate increase in glutamine [85]. Patients with PD often experience an increase in plasma pyruvate concentrations associated with changes in pyruvate dehydroginase activity [106]. An increase in dopamine catabolism is evidenced by a significant decrease in the dopamine/DOPAC (3,4-dioxyphenylacetic acid) ratio in urine and a decrease in the excretion of dopamine, 3,4-dioxyphenylalanine (DOPA), and norepinephrine, which correlates with the severity of symptoms [28]. Recent experimental studies have confirmed that a decrease in urinary DOPA, especially DOPAC, directly correlates with the degree of destruction of dopaminergic neurons in the rat brain [33].
Thus, today it is impossible to talk about any specific biochemical marker of the disease. A number of characteristic changes have been identified that are specific not only to PD, but also to a number of other diseases. Work in this direction will continue, and perhaps after some time it will be possible to select markers, the detection of which will allow the patient to be included in the risk group for PD.
Transcranial ultrasound scan of the brain
The use of transcranial sonography (TCS) in PD is based on obtaining a hyperechoic signal from the substantia nigra due to its increased iron content. Hyperechogenicity in the initial stages of PD is detected on the side contralateral to motor disorders in more than 90% of patients [43, 44, 116]. Approximately 40% of first-degree relatives of patients with PD show changes on TCS. Hyperechogenicity of the substantia nigra can also be detected in 9% of clinically healthy people. Additionally, we note that in healthy individuals with increased echogenicity of the substantia nigra, PET revealed a significant decrease in the accumulation of [18F]-fluorodopa in the striatum in 60% of cases compared to controls.
Despite little experience with the use of TCS in the diagnosis of PD, the literature has already described 8 cases of detection of hyperechogenicity of the substantia nigra with subsequent manifestation of PD symptoms over several years [42]. The undoubted advantages of the method are low cost, non-invasiveness, short research time, and the possibility of repeating the study many times over time. Perhaps, with the accumulation of sufficient experience, this method can be used as a screening examination, but its results need to be confirmed by other methods.
Olfactory research
According to the concept of H. Braak et al. [49], the neurodegenerative process in PD initially involves the olfactory bulb, anterior olfactory nucleus, dorsal nucleus of the vagal nerve (stage I), then it spreads along the brain stem, involving the locus coeruleus, raphe nuclei, areas responsible for REM sleep (stage II ), and only then moves to the substantia nigra of the striatum (stage III) [49]. Therefore, olfactory dysfunction (hyposmia, anosmia) is one of the first signs of PD. For diagnosis, an assessment of the olfactory threshold, the ability to distinguish and identify odors is carried out. A case-control study found changes in 68% of patients with early stages of PD, while in controls, loss of smell was observed in only 3% [70]. In a study of 30 people with idiopathic smell loss using TCS and SPECT, 11 showed increased echo from the substantia nigra, and 5 of these 11 patients showed decreased radioligand uptake on SPECT [108]. Olfactory dysfunction is also observed in 10–23% of healthy relatives of patients with PD [98]. When observing twins, one of whom suffered from PD, cases of the development of symptoms of parkinsonism were described in previously healthy twins who, several years earlier, had lower scores on smell tests compared to other healthy twins [86].
Transcranial magnetic stimulation
A number of studies [59,78] have shown a decrease in the time of central motor behavior (CMBT) and an increase in the amplitude of the evoked motor response (EMR). The increase in amplitude turned out to be greater, the more pronounced the symptoms of the disease were. A shortening of the VMC was associated with the possible activation of the most rapidly conducting motor neurons, and an increase in the amplitude of the MEP was associated with increased excitability of cortical and/or spinal motor neurons [61]. These changes are probably based on an imbalance of excitatory and inhibitory influences with a predominance of excitatory choline and glutamatergic systems.
Registration of saccadic eye movements
PD is characterized by changes in the parameters of saccadic eye movements, which is explained by a decrease in the inhibitory connections of the reticular part of the substantia nigra with the superior colliculus of the quadrigeminal colliculus against the background of a decrease in dopamine production [4]. Saccades are jump-like, fast, friendly, fixating eye movements that occur when moving the gaze from one stationary object to another. An oculographic examination of patients with the initial stages of PD (stages I-II according to the Hoehn and Yahr scale) reveals longer than normal average values of latent periods (the time interval from a change in the position of significant visual stimuli to the start of a saccade), as well as the time gaze movements, which is associated with an increase in the proportion of a special group of eye movements - multisaccades, when the eye reaches a target not by one, but by several (two, three or more) consecutive saccades [35, 57].
Electroencephalography (EEG)
EEG in patients with PD shows a decrease in α-activity and an increase in the power of slow rhythms (θ- and δ-) in both hemispheres [10, 11, 34, 49, 92]. The θ rhythm is most represented in the spectrum [103]. A slowdown in the electrical activity of the brain is detected already in the early stages of the disease, is more pronounced in the akinetic-rigid form and intensifies as PD progresses and the motor defect in patients worsens [9, 27, 36, 41, 107]. The main feature of the α rhythm in PD is its approach to the lower limit of the spectrum [31, 92]. A correlation has been found between the severity of akinesia and the slowing of the α-rhythm during wakefulness [105]. On the contrary, a number of authors [8, 117] in parkinsonism pointed to a tendency towards desynchronization of the background EEG with the appearance of fast rhythms with a frequency of up to 100 per 1 s. In patients with mild and moderate stages of the disease, a decrease in the power of β- and γ-activity was found, along with its increase in the θ- and α1-frequency ranges [109], and in patients with late stages of PD, an increase in β-activity was found [65].
Evoked potentials (EP)
When examining patients using visual EPs (VEPs) at the stage of hemiparkinsonism, a decrease in the maximum amplitude of late components and an increase in the latency of the early positive component of the P100 response was shown compared to the “intact” hemisphere. The asymmetry of amplitudes and latencies disappeared as the disease progressed [45, 88]. In PD, the latency of not only the P100 component, but also N75 and N145 increases, and its values correlate with the severity of motor manifestations and the duration of the disease [53, 94]. Changes in VEP are explained by biochemical and electrophysiological changes in the retina, whose neurons are rich in dopamine, which is confirmed by electroretinography data [93]. At the same time, another study of VEP on the reverse chess pattern in patients with PD, conducted by S. Ozden et al. [95], did not find any significant amplitude-temporal asymmetry of components between the more and less affected sides when stimulating the corresponding eye. There were also no correlations between these indicators and the clinical manifestations of PD with the exception of bradykinesia. When analyzing the results of the study of VEP to a flash of light, it was noted that there was no difference in indicators in patients depending on the stage of the disease.
When studying somatosensory EPs (SSEPs) in PD, a decrease in the amplitudes and an increase in the latencies of individual peaks is found, in particular, a decrease in the amplitude of the P37 and N50 peaks during stimulation of the lower extremities [112], a decrease in the amplitude of the N31 component and an increase in the latency of P44, which correlate with the age of patients [62 ]. Changes in SSEP parameters at the stage of unilateral clinical manifestations were studied; a decrease in the N30 peak was noted, while no connection was found between the amplitude-time characteristics of this component and the side of clinical manifestations [60, 75].
A study of short-latency brainstem EPs to acoustic stimulation revealed a significant increase in latency and a decrease in the amplitude parameters of the V component [120]. However, an increase in the interpeak latency of components I and V is characteristic only for PD in combination with dementia, and the group of patients without dementia (i.e., the initial stages of the disease) and controls did not have any significant differences in this indicator at all [71]. An increase in the latent period of peaks I [38] and III [58] in PD was noted.
When studying cognitive evoked potentials in PD, there is a decrease in the amplitude of the P300 potential in the parietal regions with its maximum values in the frontal leads [15] and an extension of the latent period [12]. Changes in the P300 potential are characteristic only of patients with dementia, and patients without dementia do not differ from the control group in these indicators [113]. In PD without dementia, there is an absence of interhemispheric asymmetry during nonverbal stimulation, which may indicate dysfunction of the subdominant hemisphere [15].
PD is characterized by a decrease in the amplitudes of the main components of olfactory evoked potentials until their disappearance [102] and an increase in peak latencies even in the absence of impairments in the main olfactory tests [67-69].
Electromyography and electroneuromyography
Electromyographic studies using cutaneous electrodes can reveal a number of EMG changes in patients with PD [48]. In patients with the trembling form of the disease, volley activity is recorded with high-voltage fluctuations in the biopotential of muscles at rest, similar to volleys with a frequency of 4-8 per 1 s, which reflects the rhythm of tremor. Electromyographic recording of tremor showed that volley activity is reciprocal in nature, i.e. at the moment of a pause in the agonist there is a salvo discharge in the antagonist [30, 31]. In the akinetic-rigid form of the disease, the electromyogram is of a stationary type and is formed on the basis of rhythmic asynchronous stationary activity of motor units [19]. As PD progresses, the amplitude of tremor increases and the frequency of bursts decreases [39, 87]. Low-frequency tremor is thought to have higher amplitude and longer burst duration [46, 101, 119]. As muscle tone increases in the later stages of the disease, volley activity is suppressed [26].
EMG changes can be detected in subclinical and early stages of PD [72]. They can also be detected in 17.3% of healthy middle-aged people and 26.2% of elderly people, which reflects the presence of hidden extrapyramidal insufficiency and a weakening of inhibitory suprasegmental influences with age [16, 23]. In healthy relatives of patients with parkinsonism, in 45% of cases, the presence of volley activity on the EMG is detected [13, 22]. Examination of clinically intact limbs in patients with stage I PD using EMG with spectral analysis revealed changes in 71% of cases in the upper limbs and 58% in the lower limbs [6]. These data are of some interest as a promising possibility of using this technique as a tool to facilitate the early diagnosis of PD.
The results of using stimulation myography - electroneuromyography in patients with PD are contradictory. Some authors noted a decrease in the amplitude of the M response to ENMG [3, 81]. According to the results of our studies [1], the early stages of PD are characterized by an increase in the amplitude of the M-response in the muscles of the hands and feet on the side of the onset of motor disorders, which is confirmed by the results of other studies [29, 66]. In patients with PD, the amplitude of the M-response in the hand muscles is higher than in patients with vascular parkinsonism [7]. Impulse conduction velocity (ICV) along peripheral nerves in patients with PD also undergoes changes: there is a decrease in ICV in PD, probably associated with a weakening of descending supraspinal and intrasegmental tonic impulses and facilitation of the function of α-motoneurons [3]. Increased SPI has been described in PD [7]. According to our data, in patients with the initial stages of PD, there is an increase in conduction along the motor fibers of peripheral nerves, which is manifested in an increase in SPI and a decrease in M-response latency. High SPI values are apparently explained by a decrease in descending inhibitory influences from the nigrospinal tract on the interneurons of the tonic stretch reflex and an increase in the excitability of spinal motor neurons [23, 81]. To assess the functional state of the motor neuron apparatus of the spinal cord, monosynaptic testing (H-reflex) is also used, the study of which, as a rule, indicates increased excitability of the spinal motor neuron apparatus [14, 20, 21, 25, 32, 77]. In PD, there is a decrease in the latent period, a decrease in the evocation threshold, and an increase in the amplitude of the H-response [1, 100].
Conclusion
This review shows that today there is not a single method (with the exception of inaccessible PET and SPECT options) that would allow identifying certain signs (criteria) of the disease. Perhaps in the next decade it will be possible to identify a range of additional studies that will have a sufficient level of evidence to recommend them to the list of necessary methods for diagnosing PD. These will likely be several biomarkers that are readily available for analysis. At the moment, according to the protocol for the management of patients with PD, approved by the Ministry of Health of the Russian Federation (2005), the list of medical services for PD includes only anamnesis and a neurological examination. MRI and CT are recommended to be performed in the presence of symptoms not typical for PD, in order to exclude other diseases. The development of biomarkers will significantly increase the accuracy of diagnosis in the early stages of the disease and will make it possible to identify a group at risk for this disease when identifying changes in clinically healthy people.
[] The main difficulty is the need to use short-lived labeled (radioactive) compounds, the production of which is possible only in appropriate installations.
