Parkinson's disease, also known as“Tremor paralysis”, is a neurodegenerative disease.The main cause of this disease is the degeneration and death of dopaminergic neurons in substantia nigra, which may be related to heredity, environmental factors, aging of nervous system and other factors.It is recognized that,be senileIt is the most important factor in the occurrence of Parkinson's disease. The disease has a significant high incidence in the elderly. The incidence of male is slightly higher than that of female.
The symptoms of Parkinson's disease are different, mainly showing two types of symptoms: motor and non motor.Sports symptoms includeStatic tremor、Myotonia, movement retardation and postural balance disorder.Non motor symptoms mainly includeconstipation、Anosmia、Sleep disorders, autonomic nervous dysfunction and spiritCognitive impairmentEtc.
Parkinson's disease is mainly treated bymedicationandsurgical treatment。Drug treatment includes but is not limited to monoamine oxidase type B (MAO-B) inhibitorsDopamine receptor（DR）Agonist、Catechol-O-methyltransferase (COMT) inhibitor, etc.The main surgical treatments were nucleus lesion and deep brain stimulation (DBS).
Medical research suggests that the occurrence of Parkinson's disease is related to the degeneration and death of dopaminergic neurons in the substantia nigra, but what exactly causes the degeneration and death of these neurons has not been clear, which may be related to a variety of factors, including genetic factorsenvironmental factor, nervous system aging, etc.
Genetic factor
At present, it is believed that 10% of patients have a family history, and the vast majority of patients are sporadic.
environmental factor
Industrial or agricultural toxins with similar molecular structure to the neurotoxic 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) in the environment, such as someInsecticide、herbicide、rotenoneIt may be one of the causes of Parkinson's disease.
Aging of nervous system
Some data show that after 30 years old, dopaminergic neurons in substantia nigra begin to degenerate with age, but not all of them lead to Parkinson's disease. Aging is the most important factor for Parkinson's disease.
Multifactor interaction
In addition to gene mutation leading to the onset of a small number of familial Parkinson's disease patients, gene susceptibility can increase the probability of the disease, but not necessarily the onset.
Only under the combined effect of environmental factors, nervous system aging and other factors can it lead to disease.
symptom
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The symptoms of Parkinson's disease vary from person to person. The most obvious symptom isStatic tremor, movement retardation andMyotonia, patients in the middle and late stages have postural balance disorders, and there are also some non motor symptoms before and after the onset, includingconstipation、Anosmia、Sleep disorders, autonomic nervous dysfunction and spiritCognitive impairment。
Typical symptoms are divided into two categories, one is movement symptoms, the other is non movement symptoms.
Exercise symptom
Static tremor: This kind of symptom is often the first symptom, most of which starts at the distal part of one side of the upper limb, and appears or has obvious symptoms when standing still.At the time of onset, there was a "pill rubbing" movement between the thumb and the flexing index finger.
Myotonia: The patient's limbs may appear in a state similar to a curved soft lead pipe, which is called "lead pipe like rigidity"; in patients with static tremor, intermittent pause like tremor may appear, which is like rotating gears, which is called "gear like rigidity".In severe cases, patients may have special flexion positions or postures, or even cannot take care of themselves.
Slow movement: In the early stage, it can be observed that the patient's fingers are slow in fine movements, such as unbuttoning or buttoning, tying shoelaces, etc., which is particularly obvious.
Postural balance disorder: it occurs in the middle and late stages of the disease, and it is difficult for the patient to stand up and easy to fall backward.Sometimes patients walk faster and faster with minimal steps after walking, and cannot stop in time, which is called forward gait or flustered gait.
Non motor symptoms
Sensory disturbance: Olfactory decline may occur in the early stage, and limb numbness and pain may occur in the middle and late stages of the disease.
Sleep disorders: dreamy at night, accompanied by shouting and dancing.
Autonomic nerve dysfunction: may be accompanied by constipation, hyperhidrosis, dysuria, postural hypotension, etc.
Mental disordersAbout 50% of the patients are accompanied by depression and anxiety.In the late stage of the disease, about 15%~30% of patients have cognitive impairment, even dementia.The most common mental disorder is visual hallucination, that is, hallucination.
Medical treatment
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Parkinson's disease cannot be cured, but doctors can help patients relieve symptoms by actively seeking medical advice.
Visiting department
Department of Neurology and Geriatrics
Relevant inspection
Routine examination of blood and cerebrospinal fluid: the content of high vanillic acid (HVA) in cerebrospinal fluid can be reduced, and others can be normal.
Others: The olfactory stick test is used to diagnose whether the early patients have anosmia;Transcranial ultrasound can assist in diagnosis;Cardiac m-iodobenzidine (MIBG) scintigraphy can observe the decrease of the total MIBG intake of patients, which can assist in the diagnosis of this disease.
diagnosis
The diagnosis of Parkinson's disease mainly depends on the history, clinical symptoms and signs.According to the characteristics of insidious onset and gradual progress, one side is progressive and develops to the opposite side, showing static tremor and movement retardation, which can be made after excluding atypical Parkinson's disease like symptomsclinical diagnosis。Contra left-handedDopaIf the preparation treatment is effective, it will more support the diagnosis.Routine bloodCerebrospinal fluid examinationMost of them are normal.Head CTMRIThere was no characteristic change.Olfactory examinationMost PD patients can be foundAnosmia。Take 18F dopa astracerDopa uptake function PETImagingCan display dopaminetransmitterReduction of synthesis.Dopamine administration with 125I - β - CIT and 99mTc-TRODAT-1 as tracerstransporter （DAT）Functional imagingThe number of DAT can be reduced, which can be displayed in the early stage or even subclinical stage of the disease, and can support diagnosis.However, this inspection is expensive and has not been carried out routinely.
Parkinson's disease in British Brain Bankdiagnostic criteria See Table 1.The severity of Parkinson's disease can generally be assessed by H&Y (Hoehn&Yahr) grading (see Table 2).
Table 1 Clinical diagnostic criteria for Parkinson's disease in UK Brain Bank
Step 1: Diagnosis of Parkinson's syndrome
Movement reduction: the random movement is slow at the start, and the movement speed and amplitude of repetitive movements gradually decrease
Have at least one of the following symptoms at the same time:
A Muscle rigidity
B. Static tremor (4-6 Hz)
C. Erect instability (not caused by primary vision, vestibular function, cerebellum and proprioception dysfunction)
Step 2: Exclusion criteria for Parkinson's disease
Repeated history of stroke with stepwise progression of Parkinson's symptoms
Repeated history of brain injury
Exact history of encephalitis
oculogyric crisis
At the time of symptoms, he was being treated with nerve tranquilizer
More than one relative is sick
Continuous remission
Three years after the onset, there is still strict unilateral involvement
Supranuclear gaze paralysis
Cerebellar sign
Severe autonomic nervous system involvement in early stage
Early severe dementia, accompanied by memory, language and behavior disorders
Positive pyramidal tract sign (Babinski sign+)
CT scan shows intracranial tumor or communicating hydrocephalus
Treatment with large dose of levodopa is ineffective (excluding absorption disorder)
MPTP exposure history A derivative of opioid analgesics
Step 3: Support diagnostic criteria for Parkinson's disease.Parkinson's disease can be diagnosed with three or more patients
Unilateral onset
Presence of static tremor
Progressive disease
Asymmetry with persistent symptoms, and the first side is heavier
Very good response to levodopa (70-100%)
Severe dyskinesia caused by levodopa application
The therapeutic effect of levodopa lasts for more than 5 years (including 5 years)
Clinical course more than 10 years (including 10 years)
Patients who meet the diagnostic criteria for Parkinson's syndrome in the first step can be clinically diagnosed as Parkinson's disease if they do not meet any of the criteria in the second step and meet three or more criteria in the third step.
Table 2 H&Y grading of Parkinson's disease
0=no sign
1.0=unilateral disease
1.5=unilateral disease affecting the muscles of the central axis
2.0=bilateral disease, without damage to balance
2.5=mild bilateral disease, slightly poor posture reflex, but self correction
3.0=bilateral disease, postural balance disorder, positive backward pull test
4.0=severely disabled, but able to stand or walk by oneself
5.0=unable to get up or live in a wheelchair
differential diagnosis
Parkinson's disease needs to be differentiated from secondary Parkinson's disease, primary tremor, depression, etc.
treatment
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Comprehensive treatment is adopted for Parkinson's patients, and drug treatment is the first choice,surgical treatmentAs a supplement.
General treatment
nutritional support : Some patients havelanguage barrier、DysphagiaIt affects the normal eating of patients, so it is necessary to pay special attention to the nutritional intake of patients to help them eat or provide nutritional support through vein.
General support treatment: daily exercise can improve the quality of life of patients, such as setting handrails, anti-skid pads, tableware with large handles in rooms and toilets.
Psychological support treatment: many patients with Parkinson's disease have psychological problems such as depression, which seriously affects the quality of life of patients and also affects the efficacy of drug treatment.Effective psychological counseling and antidepressant treatment for patients with Parkinson's disease is expected to achieve more satisfactory therapeutic effects.
medication
Drug treatment aims to effectively improve symptoms, improve quality of life and work ability, strive to achieve "low dose drug maintenance that can achieve satisfactory clinical effects", and strive to reduce side effects and related complications of drugs.
Treatment of early Parkinson's disease
Parkinson's disease continues to worsen once it occurs, and treatment should be started as soon as possible.
Generally, single drug treatment or low-dose combination of multiple drugs acting on different targets are used to control symptoms as much as possible and maintain the effectiveness of drugs for a longer time.
Therapeutic drugs include disease modifying drugs and symptomatic drugs.
Among them, disease modifying drugs can delay the progress of disease. The drugs with disease modifying effects mainly include type B monoamine oxidase inhibitors (MAO-B inhibitors, including selegiline+vitamin E and rasagiline), dopamine receptor agonists (DR agonists, such as praxol), and large doses of coenzyme Q10.
For late-onset patients or those with mental retardation, compound levodopa is the first choice. DR agonists, MAO-B inhibitors or catechol-O-methyltransferase (COMT) inhibitors can be added when the efficacy of drugs declines, and they should not be used as much as possibleAnticholinergic drug。
All therapeutic drugs for Parkinson's disease should be used under the guidance of the doctor, and must be added or reduced according to the doctor's advice, to avoid sudden drug withdrawal or addition, and to check regularly according to the doctor's advice.
Anticholinergic drug
It is mainly applicable to patients with obvious tremor and younger age (under 60 years old). The main drugs areBenzhexol。
Note: It is forbidden for angle closure glaucoma patients and patients with prostatic hypertrophy.
Main side effects: dry mouth, blurred vision, constipation, dysuria, affecting cognition, and serious cases includehallucination, delusion.
Amantadine
It is mainly used to improve the symptoms of hypokinesia, rigidity, tremor, etc. It may be helpful for patients with dyskinesia.
Note: Use with caution for patients with renal insufficiency, epilepsy, severe gastric ulcer, and liver disease, and it is forbidden for lactating women.
Main side effects: restlessness, confusion, reticular blue spots at the distal end of the limbs, ankle edema, etc., are relatively rare.
Compound levodopa
So far, it is still the most basic and effective drug for treating this disease.
Commonly used drugs mainly include dopamine hydrazine and carbazodidopa.
Levodopa methyl ester and ethyl ester have good effects on tremor, rigidity and bradykinesia;Water solvent is suitable for patients with morning stiffness, "off" status after meals, and dysphagia;Levodopa methyl ester and ethyl ester are suitable for patients with severe motor complications in late stage.
Note: Patients with active peptic ulcer should use it with caution, and patients with angle closure glaucoma and psychosis should not use it.
Main side effects: including peripheral nerve symptoms and central nerve symptoms. The former is nausea, vomiting, hypotension, arrhythmia (occasionally seen), while the latter has symptom fluctuations, dyskinesia, and mental symptoms.
Dopamine receptor (DR) agonist
It is applicable to early onset patients.
At present, most non ergot DR agonists are recommended as the first choice of drugs, while ergot is no longer recommended for use.
Non ergot includes Pramipexole, Robiniro, Vibedil, Rotigotine and Apomorphine.
Main side effects: Similar to compound levodopa, the difference is that the incidence of symptom fluctuation and dyskinesia is low, while the incidence of ankle edema and mental disorder due to postural hypotension is high.
Monoamine oxidase type B (MAO-B) inhibitor
Combined with compound levodopa can enhance the curative effect and improve the fluctuation of symptoms;Single use has mild symptom improvement effect.
Note: Gastric ulcer patients should be cautious and should not be used together with serotonin reuptake inhibitor (SSRI).
Catechol-O-methyltransferase (COMT) inhibitor
In the early stage of the disease, the first choice is entacapone dipoba tablet to improve symptoms.
When the curative effect of compound levodopa in the middle and late stage of the disease declines, the symptoms can be further improved by adding the treatment of Entocarbon or Tokamine.
Main side effects: diarrhea, headache, hyperhidrosis, dry mouth, elevated transaminase, abdominal pain, yellow urine, etc;Tokampone may cause liver damage, so liver function should be closely monitored, especially three months before use.
Treatment of advanced Parkinson's disease
The manifestations of PD in the middle and late stages are very complex, including the progress of the disease itself, side effects of drugs, sports complications, etc.
The treatment should not only continue to improve the movement symptoms, but also properly deal with the movement complications and non movement symptoms.
Treatment of sports complications
Movement complications include symptom fluctuation and dyskinesia.
The former mainly includes drug end deterioration and switching phenomenon, while the latter includes drug peak dyskinesia, biphasic dyskinesia, and dystonia, which can be improved by adjusting the number of medication, drug type, drug dose, dosage form, or combined use of drugs. Deep brain stimulation (DBS) and other surgical treatments are also helpful.
Treatment of postural balance disorder
Postural balance disorder is the most common cause of PD patients' wrestling, and there is no effective treatment. Adjusting the dosage of drugs or adding drugs is occasionally effective.
It may be helpful to take the initiative to adjust the body's center of gravity, stride, step, listen to music, listen to commands or beat time to walk, or move across objects.
If necessary, use a wheelchair and protect it.
Treatment of non motor symptoms
It includes sensory disorders, autonomic dysfunction, mental disorders, etc.
Early drug treatment is effective, while long-term use of drugs will significantly reduce the efficacy. When the end of the drug worsens or the phenomenon of switching occurs, surgical treatment can be considered;Patients with severe symptom fluctuations or dyskinesia may also consider surgical treatment.
The operation can significantly improve the motor symptoms, especially for limb tremor and myotonia, but it has no obvious effect on physical axis symptoms such as posture and gait disorders.
The operation can not cure the disease, so drug treatment is still needed after the operation, but the dosage can be reduced appropriately.
TCM treatment
Traditional Chinese medicine, acupuncture and other treatments can play a positive role in improving symptoms.
Other treatments
Rehabilitation treatment: According to the movement disorder (such as gait disorder, posture balance disorder, language or/andDysphagiaAnd so on) carry out corresponding rehabilitation training, such asTaiji boxing、Aerobics、joggingAs well as gait training, language adjustment training, posture balance training, etc.
Frontier treatment
Some clinical trials have shown that transplanting brain nigral cells from allogeneic embryos into the striatum of patients can correct the lack of dopamine transmitters and alleviate the motor symptoms of Parkinson's disease, but this technology has the problems of limited donor sources and ethical problems.
Stem cell transplantation (including induced pluripotent stem cells, neural stem cells, embryonic stem cells, bone marrow stromal stem cells, etc.), combined with neurotrophic factor gene therapy is a promising new therapy, but it is still in the clinical research stage.
prognosis
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The disease is still incurable.Most patients can continue to work and maintain a better quality of life with reasonable symptomatic treatment.Late stage patients may have general stiffness, which may cause difficulty in movement and finally lie in bed.It is often life-threatening due to complications such as pneumonia.
complication
In the early stage of the disease, the patients are prone to fall and other accidents due to their movement disorders, sometimes resulting in fractures;As the disease progresses, the late patients lose their ability to take care of themselves. After long-term bed rest, they may lead to serious complications such as pneumonia, urinary system infection, asphyxia, bedsores, etc.
prevention
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There is no effectivepreventive measurePrevent the occurrence and progress of disease.When patients have clinical symptoms, substantia nigra dopaminergicneuronAt least 50% died,StriatumThe content of DA decreased by more than 80%.Therefore, early discoveryPreclinicalPatients and take effective preventive measures to preventDopaminergic neuronThe occurrence and progress of the disease can be prevented only by the death of sex change.How to find preclinical patients early has become one of the hot spots in the field of Parkinson's disease research.Gene mutations andREM sleepBehavioral disorderThe non motor symptoms of PD, such as hypoesthesia, can appear several years before the onset of motor symptoms, which may be the early biology of PDMarkers。MultipleBiomarkersThe accumulation of may increase the risk of PD.Protective drugs for dopaminergic neurons are still under study.epidemiologyEvidence suggests three drinks a dayGreen TeaIt can reduce the risk of Parkinson's disease.vitamin E、Coenzyme Q10as well asfish oilIt may have a protective effect on neurons.
Disease care
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The diet of patients with Parkinson's disease has no special requirements.Patients taking levodopa preparations should be separated from their meals, and should be administered 1 hour before meals or 1 and a half hours after meals.Patients with constipation should drink more water and eat more food rich in fiber.Proper exercise for patientsfunctional recovery There is some help.Recent research shows that taijiquan has a great effect on patientsBalance functionto be helpful to.In the early stage, patients can take care of their daily life by themselves. In the middle stage, most patients need some help.The late patients need care in daily life.Dysphagia, drinking waterCough% of patients can giveNasal feedingDiet.Those who have been in bed for a long time should turn over and pat their backs regularly to avoidbedsoreandHypostatic pneumoniaOccurrence of.urinary incontinenceCatheterization is required.
Anti Papa Reading Materials
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On April 1, 2022, as the first dictionary anti pascal book in China《Anti pascal dictionary》Officially released for Parkinson's disease patients and their families from now onFreeApplication channel.This book is written byMedtronic It invited 25 experts in the field of Parkinson's disease in China to participate in the editorial work, aiming to improve the quality of Parkinson's disease patients, familiesGrass roots doctorsAnd the general public's understanding of Parkinson's disease and scientific treatment methods to avoid falling into a misunderstanding.
Reflection on the viewpoint of pathogenicity
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It has been 200 years since Parkinson's disease was discovered.Although mankind has made great progress in many diseaseshealthyanddiseaseThe understanding of the nature of Parkinson's disease is constantly deepening, but for Parkinson's diseaseAlzheimer's diseaseetc.Neurodegenerative disease, medicine is still powerless.2013Nobel Prize in Physiology or Medicine winnerRandy W. Schekman (Randy Schekman) said thatPathologyFactor, "we still know very little".In the past decades, the scientific community has always understood Parkinson's disease as a disease caused by a single factor, and hopes to invent a singleSpecific drugTo treat it.But such attempts have not been successful so far.
Alzheimer diseaseBermuda, known as medical research”。In recent decades, people have carried out a series of drug research and development against the two major pathological hypotheses of this disease - A β hypothesis and Tau protein hypothesis, but all failed.
Beta amyloid protein（Aβ）There is no doubt thatAlzheimer diseaseStudy the "focus stars" in history.Research shows that almost allAlzheimer diseasePatient'sBrain cellIn China, there will be different degrees ofAmyloid depositionThis deposit can directly poison cells and destroy neurotransmission, and plays a very important role in the progression of disease.
In September 2016《natural》The magazine reported the treatment developed by a company in the United States in the form of a cover articleAlzheimer diseaseNew drugPhase I clinical trialAs a result, it is confirmed that this drug can effectively eliminateBeta amyloid protein(A β) deposition.In June 2021,US Food and Drug Administration（FDA）It was announced that the approval of the drug to market was accelerated, but this decision caused an uproar.Because before that,FDAAllow the company to skip directlyPhase II clinical trial, opened two itemsPhase III clinical trial, but the results are not optimistic, twoexperimental data Contradiction.In March 2019, these two Phase III clinical trialsWas terminated early.Therefore, FDA approved this drug not because it showed a clear therapeutic effect, but because it reduced the deposition of A β, which is considered to be an important pathological feature of Alzheimer's disease, so it was considered "likely" to be beneficial to patients.
For people who understand Parkinson's disease as a disease caused by a single factormodern medicineThese difficulties《Principles of Systems Medicine》Think: throughout todayMedical InstituteChallenges, whetherDisease spectrumThe transformation of the government, or the problems caused by more and more excessive intervention, andGenetic defectThe complexity of the relationship between and disease all points to a common basic point of view, which is the causal explanation of disease that was formed in the 19th century and has continued to this day.If the disease is really caused by one or several reasons, it is certainly not wrong to focus on finding the cause and removing it through intervention;But if not, then everything is different.In other words, today there are sufficient reasons for us to suspect that the treatment of diseases may not be a process of finding the causes and removing them in essence.
research findings
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In 2022, a study published in Nature Neuroscience identified the "identity" of these cells through a new technology.U.S.ABode InstituteEvan Macosko team ofRNASequencing technology, allowing researchers to analyze cells in the tissue separately to determine which genes are active and which are producedprotein。The Macosko team observed the brains of eight non Parkinson's patients (who agreed to donate their brains before death for research)Substantia nigra10 dopamine producing cell subtypes were found.Then the researchers used the same technique to analyze 10 people who died of Parkinson's disease orDementia with Lewy body(Clinical and pathological manifestations are similar to Parkinson's disease and Alzheimer's disease). The number of only one brain cell subtype has decreased, indicating that many cells of this subtype have died during the survival of patients.
The researchers pointed out that there are about 100000 cells of this subtype in the brain of healthy adults."This is a very small subset, and looking for them is like looking for a needle in a haystack," Macosko said.
Macosko said that the above findings will help people better understand the etiology of Parkinson's disease and help evaluate potential treatment methods.For example, inPetri dishThe cells were cultured in medium for testing new drugs.
In 2022,SwitzerlandFederal Institute of Technology, LausanneResearchers used the new neurorobot platform and electrode measurement to decode how Parkinson's disease causes brain disorder and impairs walking of patientsAthletic abilityOf.This discovery reveals how the hypothalamic nucleus region of the brain coordinates the activation of leg muscles, and proposes an algorithm that can detect patients' "freezing" and other walking obstacles。The research results, published in Science Translational Medicine, revealed the key principle of hypothalamic nucleus dynamic coding walking and opened up the way to operate with these signalsneural prostheses System to improve the possibility of walking in patients with Parkinson's disease.
In December 2022, it was learned from the Primate Transformation Medical Research Institute of Kunming University of Science and Technology that Li Tianqing and Ji Weizhi's team had made important progress in the application of genetically engineered mesenchymal stem cells in the treatment of Parkinson's disease.Relevant research results were published online in the international journal Nature Partner Journal – Parkinson's Disease.
The team of Li Tianqing and Ji Weizhi spent eight years to develop genetically engineered mesenchymal stem cells for the treatment of Parkinson's disease that can secrete dopamine neurotransmitters in a sustained and stable manner. After transplantation into Parkinson's disease models in rats and monkeys, they can achieve the in situ reconstruction of the midbrain dopamine circuit by restoring the striatum dopamine level,It can quickly recover the motor and non motor impairment defects of monkey models with acute and chronic Parkinson's disease.The evaluation of the results for five years has proved the safety and effectiveness of this method, provided an important new strategy for the treatment of the disease, and can provide a stable and repeatable "off the shelf" cell source, showing the great potential of genetic engineering mesenchymal stem cells in the future clinical treatment of Parkinson's disease.The reviewer believes that "this research is an important contribution to the field of cell therapy for Parkinson's disease".
In August 2023, it was reported that the first neurosurgical operation using autologous cells derived from induced neural stem cells (iNSC-DAP) to treat Parkinson's disease was successfully completed in Xuanwu Hospital of Capital Medical University.It is reported that the successful implementation of this operation is a major breakthrough in the treatment of neurodegenerative diseases and another important progress of stem cells in the field of treatment of nervous system diseases.
