Introduction: Parkinson's disease, also known as idiopathic Parkinson's disease (PD), referred to as Parkinson's disease, also known as paralysis agitans (shaking palsy), is a common neurodegenerative disease in the elderly. The most common extrapyramidal disease in the elderly. The main lesions are in the substantia nigra and striatum pathways, and dopamine production is reduced. The prevalence rate of people over 65 years old is 1000/100,000. With age, men are slightly more than women. The main clinical features of the disease: resting tremor, slowness and reduction of movement, increased muscle tone, and instability of posture are the main features. Causes: (1) The cause of idiopathic Parkinson's disease has not been known so far. Some central nervous system degenerative diseases with Parkinson's disease symptoms, mainly degeneration of different parts of the central nervous system, there are other clinical features, it can be called symptomatic Parkinson disease, such as progressive supranuclear palsy (PSP), lines Sexual substantia nigra degeneration (SND), Shy-Drager syndrome (SDS) and olive pons cerebellar atrophy (OPCA). There are also some diseases or factors that can produce clinical symptoms similar to PD, such as infection, drugs (dopamine receptor blockers, etc.), poisons (MPTP, carbon monoxide, manganese, etc.), vascular (multiple cerebral infarction) and brain trauma. Etc., clinically known as Parkinson's syndrome (Palkinsonism). So far, the cause of PD remains unclear. Current research tends to be associated with a combination of ageing, genetic susceptibility, and exposure to environmental toxins. 1) Ageing: Parkinson mainly occurs in middle-aged and elderly people. It is rare to have a disease before the age of 40, suggesting that ageing is related to the disease. Studies have found that from the age of 30, dopaminergic neurons, tyrosine oxidase and dopa decarboxylase activity, striatum dopamine transmitter levels gradually decrease with age. However, only a small number of elderly people suffer from this disease, indicating that physiological dopaminergic neurons are not enough to cause disease, and age aging is only a trigger for the onset of this disease. 2) Environmental factors: Epidemiological survey results show that there is a regional difference in the prevalence of Parkinson's disease, so people suspect that there may be some toxic substances in the environment, which damage the brain's neurons. 3) Genetic susceptibility. In recent years, Alα53THr mutation of a common nuclear gene has been found in patients with familial Parkinson's disease. But it has not been confirmed many times in the future. 4) Family hereditary: In the long-term practice, medical scientists found that Parkinson's disease seems to have a tendency to family aggregation. The family members of patients with Parkinson's disease have a higher incidence than their normal counterparts. It is now widely accepted that Parkinson is not a single factor and multiple factors may be involved. Genetic factors can increase the susceptibility to disease, and only through interaction with environmental factors and aging, through oxidative stress, mitochondrial failure, calcium overload, excitatory amino acid toxicity, apoptosis, immune abnormalities and other mechanisms lead to black A large number of degeneration of dopaminergic neurons are lost and the disease occurs. (B) pathogenesis 1. The pathogenesis is very complicated and may be related to the following factors. (1) Age aging: PD mainly occurs in middle-aged and elderly people. It is rare before 40 years old, suggesting that aging is related to the disease. The study found that from the age of 30, the activity of DA neurons, tyrosine hydroxylase (TH) and dopa decarboxylase (DDC), striatum DA transmitter decreased, DAD1 and D2 receptor density decreased. However, the elderly suffer from PD, after all, is a minority, indicating that physiological DA can degenerate neurons to cause the disease. In fact, only the substantia nigra DA neurons can be reduced by more than 50%, and the striatum DA transmitters are reduced by more than 80%. The symptoms of PD will appear in the clinic, and aging is only the triggering factor of PD. (2) Environmental factors: Epidemiological surveys show that long-term exposure to pesticides, herbicides or certain industrial chemicals may be a risk factor for PD. In the early 1980s, some drug users in California used a neurotoxic substance, the pyridine derivative 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), which appeared to be like primary. Some pathological changes, biochemical changes, symptoms and drug treatment responses of PD have similar effects on monkeys injected with MPTP. Neurotropic MPTP and certain insecticides and herbicides may inhibit the activity of NADH-CoQ reductase (complex I) in the mitochondrial respiratory chain of the substantia nigra, resulting in decreased ATP production and increased free radical production, leading to degeneration of DA neurons. There is significant lipid peroxidation in PD substantia nigra, and reduced glutathione is significantly decreased, suggesting that antioxidant mechanisms and oxidative stress may be related to PD. (3) Genetic factors: About 10% of patients have a family history, with incompletely explicit autosomal dominant or recessive inheritance, and the rest are sporadic PD. Twin-consistent studies have shown that genetic factors may play an important role in some young (<40 years old) patients. It has been determined that 10 single genes such as PARK 1～10 are related to PD, and it has been confirmed that three gene products are related to familial PD: 1α-synuclein is a mutation of PARK1 gene, and the gene is located on chromosome 4 long arm 4q21～ 23, α-synuclein may increase the sensitivity of DA neurons to neurotoxin; 2 Parkin is a mutation of PARK2 gene, located on chromosome 6 long arm 6q25.2~27; 3 ubiquitin C-terminal hydroxylase- L1 is a mutation in the PARK5 gene and is located on the short arm 4p14 of chromosome 4. The cytochrome P45O2D6 gene and some mitochondrial DNA mutations may be one of the susceptible factors of PD, which may reduce the activity of P450 enzyme, impair the detoxification function of the liver, and easily cause damage to the nigrostriae by toxins such as MPTP. (4) Oxidative stress and free radical formation: Free radicals can cause lipid peroxidation (LPO) of unsaturated fatty acids, which can oxidize damage to proteins and DNA, leading to cell degeneration and death. Due to the increased activity of type B monoamine oxidase (MAO-B), patients with PD can produce excess OH groups and destroy cell membranes. At the same time of oxidation, the DA oxidation product in the substantia nigra cells polymerizes to form neuromelanin, which combines with iron to produce a Fenton reaction to form OH. Under normal circumstances, there are enough antioxidants in the cells, such as glutathione (GSH), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) in the brain, DA Oxidation produces free radicals that do not produce oxidative stress and are protected from free radical damage. PD patients have reduced GSH and increased LPO in the substantia nigra, increased iron ion (Fe2) concentration and decreased ferritin content, making the substantia nigra a site susceptible to oxidative stress. (5) Mitochondrial function defects: In recent years, it has been found that mitochondrial function defects play an important role in the pathogenesis of PD. The understanding of mitochondrial dysfunction in PD patients stems from the study of the mechanism of action of MPTP, which causes Parkinson's disease by inhibiting the activity of the mitochondrial respiratory chain complex I. In vitro experiments confirmed that MPTP active ingredient MPP can cause a decrease in mitochondrial membrane potential (ΔΨm) and an increase in oxygen free radical production in MES 23.5 cells. The activity of mitochondrial complex I in the patients with PD can be reduced by 32% to 38%, and the decrease in the activity of the complex alpha increases the sensitivity of the nigral cells to free radical damage. No change in complex I activity was observed in the substantia nigra of patients with multiple system atrophy and progressive supranuclear palsy, suggesting that the decrease in PD substantia nigra I activity may be a relative change in PD. The presence of mitochondrial dysfunction in PD patients may be related to genetic and environmental factors. Studies suggest that mitochondrial DNA mutations exist in PD patients. Complex I is encoded by both nucleus and mitochondria. Any fragment defect in both groups can affect complex I function. . (6) Excitotoxicity: Some authors used microdialysis and HPLC to find that the content of excitatory amino acids (glutamate, aspartic acid) in the striatum of PD monkey model prepared by MPTP was significantly increased. If the extracellular space glutamate concentration is abnormally increased, the receptor will be over-stimulated and it will have a significant toxic effect on the CNS. Animal experiments have found that intracerebral injection of trace glutamate can cause large neuronal necrosis. Glutamate neurotoxicity acts through receptors. NMDA receptor-mediated excitotoxicity is associated with DA neuron degeneration. Glutamic acid can damage nerve cells by activating nitric oxide (NO) by activating NMDA receptors, and releasing more excitatory amino acids, further aggravating neuronal damage. (7) Cytotoxicity of calcium: human aging may be associated with increased concentration of free Ca2 in nerve cells, decreased Ca2/Mg2-ATPase activity, and decreased mitochondrial calcium storage capacity. Changes in intracellular Ca2 concentration affect many important functions of neurons, such as cytoskeletal maintenance, neurotransmitter function, protein synthesis and Ca2-mediated enzyme activity, calcium-binding protein, especially 28KD vitamin D-dependent calcium-binding protein (Calbindin-D28K) May play an important role, related to calcium / magnesium - ATPase activation, with neuroprotective effects. Icopini and Christakos reported that the content of Calbindin-D28K and mRNA in the substantia nigra, hippocampus and dorsal nucleus of PD patients were significantly lower than those in normal subjects, suggesting that the decrease of calbindin gene expression may also lead to cytotoxicity. (8) Immunological abnormalities: Abramsky (1978) proposed that PD is associated with immune abnormalities. Clinical studies have found that PD patients have decreased cellular immune function and decreased IL-1 activity. McRae-Degueurce et al reported the presence of anti-DA neuron antibodies in cerebrospinal fluid (CSF) of PD patients. Cell culture found that PD plasma and CSF inhibited the function and growth of DA neurons in the midbrain of rats. Stereotactic injection of blood IgG into PD patients was observed, and the tyrosine hydroxylase (TH) and DA neurons were significantly reduced, suggesting that it may initiate or participate in immune-mediated nigral cell damage. Tumor necrosis factor-α (TNF-α), IL-6, epidermal growth factor (EGF), transfer growth factor-α (TGF-α) and β2-microglobulin (β2-MG) may be involved in the pathogenesis of PD. (9) Apoptosis: Studies have shown that there are apoptosis, free radicals, neurotoxins and neurotrophic factors in the pathogenesis of PD. Agid (1995) detected the apoptotic morphological and biochemical features of DA neurons in patients with PD, and found that about 5 neurons in the brain of PD patients have characteristic apoptosis and TNF-α receptor (α-TN- FR) and bcl-2 proto-oncogene expression, apoptosis may be a basic step in the degeneration of DA neurons. It is generally believed that PD is not a single factor causing disease and may involve multiple factors. Genetic factors increase the susceptibility to disease, and under the combined action of environmental factors and ageing, the degeneration of DA neurons can be induced by oxidative stress, mitochondrial failure, calcium overload, excitatory amino acid toxicity and apoptosis. Causes the disease. 2. Pathological changes The main pathological changes of PD are degeneration and loss of pigment-containing neurons, and the DA neurons of the substantia nigra pars compacta are most prominent. Microscopically, neuronal cells were reduced, melanocytes in the substantia nigra disappeared, and melanin particles were scattered in tissues and macrophages, with varying degrees of gliosis. Normal human substantia nigra cells decrease with age. When the substantia nigra cells are 80 years old, they are reduced from the original 425,000 to 200,000, and there are less than 100,000 PD patients. When symptoms appear, DA neurons can lose more than 50%, blue spots. Mild changes were also observed in the nucleus of the nucleus, the dorsal nucleus of the vagus nerve, the globus pallidus, the putamen, the caudate nucleus, and the subthalamic nucleus. Lewy corpuscles in the cytoplasm of residual neurons are important pathological features of this disease. Lewy bodies are glass-like masses composed of cytoplasmic proteins with a dense core in the center and a filamentous halo around them. . A cell can sometimes be seen in a number of different sizes of Lewy bodies, found in about 10% of residual cells, black matter is obvious, globus, striatum and blue spots are also visible, α-synuclein and ubiquitin are Lewy small An important component of the body. 3. Neurochemical changes DA and acetylcholine (Ach) act as two important neurotransmitters in the striatum, and their functions are mutually antagonistic. Maintaining the balance between the two plays an important role in regulating the activity of the basal ganglia. The DA transmitter pathway in the brain is mainly a substantia nigra-striate system. The DA neurons of the substantia nigra pars compacta take L-tyrosine from the bloodstream and form levodosine under the action of intracellular tyrosine hydroxylase (TH). L-dopa; further produces dopamine (DA) by dopamine decarboxylase (DDC); through the substantia nigra-striatum bundle, DA acts on the putamen, caudate nucleus, and is decomposed into High vanillic acid (HVA). Due to a decrease in TH and DDC in idiopathic Parkinson's disease, DA production is reduced (L-dopa is reduced by L-tyrosine production, and DA production is decreased). Monoamine oxidase B (MAO-B) inhibitor can reduce DA catabolism in neurons and increase DA content in brain. The catechol-oxygen-methyltransferase (COMT) inhibitor reduces peripheral metabolism of L-dopa and maintains a stable plasma concentration of L-dopa. Degeneration of the substantia nigra DA neurons in PD patients, degeneration of the nigrostriatal striatum DA pathway, and a significant decrease in the striatum DA content (>80%), which makes the Ach system function relatively hyperactive, leading to increased muscle tone and reduced movement. The biochemical basis of the symptoms of exercise. In recent years, the DA content in the midbrain-marginal system and the midbrain-cortex system has also been significantly reduced, which may lead to advanced neurological activity disorders such as mental decline, behavioral abnormalities, and speech disorder. The degree of DA transmitter reduction is consistent with the patient's symptom severity. The early stage of the lesion is increased by the rate of DA renewal (pre-synaptic compensation) and the DA receptor is hyper-sensitive (post-synaptic compensation), and the clinical symptoms are not obvious. Reimbursement), typical PD symptoms (decompensation period) with disease progression. Other basal ganglia or neuropeptides such as norepinephrine (NE), serotonin (5-HT), substance P (SP), enkephalin (ENK), and somatostatin (SS) also vary. Symptoms: Clinical manifestations of PD usually occur between the ages of 40 and 70 years. After 60 years of age, the incidence is increased. Before the age of 30, the incidence is rare. In a group of 380 patients with PD, only 4 cases; slightly more males. Insidious onset, slow development, mainly manifested in resting tremor, increased muscle tone and retarded exercise, etc., the symptoms appear first and then vary from person to person. The first symptom was the most tremor (60% to 70%), followed by walking disorders (12%), myotonia (10%), and bradykinesia (10%). Symptoms often start from one upper limb, gradually affecting the ipsilateral lower limb, contralateral upper limb and lower limb, showing an "N" shape progression (65% to 70%); 25% to 30% of cases can start from one lower limb, two Lateral lower limbs are rare at the same time. In many cases, there are still left and right differences in the symptoms of advanced disease. Read more...
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