Parkinson's disease: risk factors and approaches to therapy
Neurologist Marina Nodel on Parkinsonism syndrome, dopamine deficiency and the development of neuroprotection methods
Parkinson's disease is a chronic progressive neurodegenerative disease of the brain. Descriptions of the manifestations of the disease were found in the writings of ancient Indian doctors – Ayurveda. But the English physician James Parkinson was recognized as the discoverer of the disease, who published in 1817 the work "Essay on trembling paralysis", where he described several cases and noted a number of characteristic symptoms of the disease. A more complete description of the clinical picture of the disease was made in the 1860s by the French neurologist Jean Martin Charcot, who suggested naming the disease after James Parkinson.
The first page of James Parkinson's "Essay on trembling Paralysis" // wikipedia.org
Symptoms of Parkinson's disease
Parkinsonism syndrome is a key one in the clinical picture of the disease. It manifests itself by slowing down the pace and reducing the amplitude of movements (bradykinesia) in combination with increased muscle tone and / or trembling (tremor) of the arms, legs, chin. The key violation is precisely bradykinesia, and tremor in a quarter of cases of the disease is completely absent.
Bradykinesia can be manifested by a decrease in the volume of the voice and a violation of articulation, impoverishment of facial expressions, a decrease in the size of letters when writing, restriction of performing small movements with fingers, Parkinsonian gait (decrease in height and length of step), slowing down and difficulty getting up from a chair, turns in bed. Bradykinesia, changes in muscle tone and posture are often manifested by pain or discomfort in the arm (shoulder joint), back. With Parkinsonism syndrome in the late stages of the disease, instability is combined with possible falls, violations of the beginning of walking, episodes of involuntary stops ("freezes") when walking.
Severe tremor of the left hand in Parkinson's disease // wikipedia.org
There is a form where tremor prevails (mainly a trembling form), akinetic-rigid (without tremor) and mixed. It is noted that the akinetic-rigid form often proceeds more heavily – with a relatively rapid increase in walking disorders, instability, disorders in the intellectual sphere. Parkinson's disease is characterized by significant variability in the course of the disease with varying degrees of severity of motor and non-motor manifestations.
Causes of Parkinson's disease
There is no definite answer to the question about the root cause of Parkinson's disease yet. Researchers continue to study the causes of premature aging and death of nerve cells. It is believed that the development of the disease is caused by the interaction of hereditary predisposition, external neurotoxic factors and aging processes. Some inherited genes increase the vulnerability of nerve cells to the effects of damaging environmental factors.
External harmful factors include salts of certain metals, organic solvents, pesticides and herbicides. The list of substances potentially dangerous for nerve cells continues to expand. As a result of this interaction, a cascade of neuropathological reactions is triggered. This is how a widespread neurodegenerative process is formed, affecting various parts of the brain and peripheral autonomic nervous system as the disease progresses.
Taurus Levi
An important milestone in the study of Parkinson's disease is associated with the discovery of the morphological substrate of the disease. In 1919, the Soviet neurologist Konstantin Tretyakov linked the development of Parkinsonism symptoms with the loss of special brain cells – pigment neurons of the substantia nigra of the trunk, as well as with the deposition of pathological inclusions in these cells. Tretyakov suggested calling neuronal inclusions Levi's corpuscles in honor of the German morphologist Friedrich Levi, who previously described similar changes in Parkinsonism in other parts of the brain stem. This discovery is fundamental in understanding the pathological changes underlying the motor symptoms of the disease.
Levi's corpuscles in the black substance of the midbrain // Suraj Rajan, wikipedia.org
Dopamine deficiency
The occurrence of motor manifestations of Parkinson's disease is associated with the premature death of nerve cells in the brain that produce dopamine. In 1958, Swedish pharmacologist Arvid Karlsson, conducting experiments on animals, proved the significant role of dopamine in the brain. Half a century later, he received the Nobel Prize for this discovery. A significant decrease in dopamine content in the median structures of the brain (basal ganglia) in patients who died from Parkinson's disease was shown in 1961 by the Austrian scientist Oleg Gornikevich.
Dopamine is a neurochemical substance necessary for the transmission of nerve impulses in brain cells that provide the ability to move. Lack of dopamine, in turn, is the main cause of motor disorders in patients. However, the deficiency of dopamine production is manifested not only by disorders in the motor sphere. Dopamine is involved in the regulation of emotions, motivational components of behavior, cognitive processes. Therefore, disorders of the emotional, intellectual sphere, behavior are very characteristic of Parkinson's disease.
Morphology in Parkinson's disease
In recent decades, the understanding of morphology in Parkinson's disease has been significantly expanded, evidence of the prevalence of the pathological process in this disease has been obtained. In addition to dopamine deficiency, the "suffering" of other neurochemical systems of the brain has also been proven. Thus, the degeneration of the nuclei of the brain stem that produce other neurotransmitters (serotonin, norepinephrine, acetylcholine) is associated with the development of depression, anxiety, apathy, night sleep disorders and increased daytime sleepiness, impaired intellectual functions. These symptoms in different combinations at different stages of the disease occur in 30-80% of patients and can outpace the motor classic symptoms of the disease by 5-10 years, forming the so-called pre-motor stage of the disease. Parkinson's disease can begin with non-dopaminergic brain structures.
Diagnostic methods
The diagnosis of "Parkinson's disease" is established based on the analysis of the medical history – anamnesis and clinical examination data. Neuroimaging of the brain (magnetic resonance imaging) is used to exclude other diseases (brain tumors, hydrocephalus, dyscirculatory encephalopathy) and is prescribed mainly when atypical, uncharacteristic for Parkinson's disease anamnestic data or clinical symptoms are detected.
Modern neuroimaging methods (single-photon emission computed tomography, positron emission tomography) with the introduction of various radiopharmaceuticals allow us to assess the functional state of the endings of dopamine-producing neurons in the brain by the degree of absorption of radioactive dopamine analogues. These methods are mainly used in scientific research, and can be used in diagnostically difficult cases. But the high cost of modern neuroimaging methods does not allow them to be widely used in clinical practice.
To confirm the diagnosis of "Parkinson's disease", especially with initial manifestations, an ultrasound examination – transcranial sonography can be performed. At the same time, the marker of Parkinson's disease is an increase in the intensity of the signal (hyperechogenicity) from the substantia nigra (sensitivity and specificity of the method is 90%). Unlike functional neuroimaging methods, transcranial sonography is safe and simple: radiopharmaceuticals are not administered intravenously. It is affordable from an economic point of view.
Transcranial Sonography // Journal of Diagnostic Imaging in Therapy, flickr.com
Therapy of Parkinson's disease
The main approach to the therapy of Parkinson's disease is symptomatic, that is, the effect on the symptoms of the disease in order to reduce their severity. A new era in the treatment of patients with Parkinson's disease began in the 1960s, when levodopa, a metabolic precursor to dopamine, began to be used. Drugs containing levodopa are still the most effective means for the treatment of Parkinson's disease. Other drugs that functionally replace the lack of dopamine are also used: dopamine receptor agonists, amantadines, drugs that reduce the destruction (catabolism) of dopamine and levodopa.
The treatment program of each patient is developed individually, taking into account the degree of functional maladaptation, age, severity of individual symptoms of the disease, the presence of side effects of therapy and concomitant diseases. The goal of therapy is to maximize the recovery of daily activity with the use of the lowest possible doses of drugs that are safe for the patient. In the case of non–motor manifestations of the disease – depression, sleep disorders - an assessment of the nature and severity of symptoms and appropriate therapy is required.
Surgical treatment (electrical stimulation of deep brain structures involved in the disease) is used at the advanced stages of the disease in cases where the possibilities of drug therapy are limited as a result of the progression of the disease or adverse events of therapy. Operations can reduce the manifestations of the disease and reduce the dose of drug therapy. Great importance is attached to motor activity. It is proved that regular dosed physical activity contributes to a more favorable course of the disease.
Electrical stimulation of deep brain structures in Parkinson's disease // wikipedia.org
Modern studies of parkinsonism
Modern research on Parkinson's disease covers a variety of aspects. One of the actively developed areas of study of Parkinson's disease is the clarification of the molecular mechanisms of the pathogenesis of the disease, the identification of biochemical, clinical markers of the early stages of the disease. Understanding these aspects is promising with regard to the development and implementation of effective neuroprotection methods – approaches aimed at slowing down neurodegeneration. Genetic, morphofunctional, and clinical factors that allow predicting the features of the course of the disease are being studied. The etiological features of the pathophysiology of non-motor disorders of the disease, the degree of their influence on the quality of life of patients, approaches to their prevention and treatment are clarified.
For symptomatic therapy, more advanced dosage forms are being developed that provide long-term, physiological activation of dopaminergic receptors of the basal ganglia. Prerequisites for this task are the features of the pharmacokinetics of levodopa with a short half-life of the drug from blood plasma, slowing the motility of the gastrointestinal tract in patients with Parkinson's disease with impaired absorption of the drug in the late stages of the disease.
About the author: Marina Nodel – Doctor of Medical Sciences, Associate Professor of the Department of Nervous Diseases of the Faculty of Medicine, leading researcher of the Research Institute of Neurology of the First Moscow State Medical University. Sechenova, Head of the Center for Parkinson's Disease and Motor Disorders of the Russian Scientific and Clinical Gerontology Center.
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01.03.2017