Parkinson's Disease - Causes and Pathogenesis

Parkinson's disease is a progressive neurological disorder characterized primarily by motor symptoms such as rigidity, hypokinesia, and tremor.

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Causes of Parkinson's Disease

The development of Parkinsonism is multifactorial and can be associated with the effects of certain toxins, such as manganese, carbon monoxide, and MPTF.

External causes

Manganese. Parkinsonism in experimental animals and miners can occur under the influence of high concentrations of manganese. Long-term and chronic occupational exposure to Mn (> 1 mg/m3) is a risk factor for Parkinson's disease. The pathomorphological basis of manganese parkinsonism is the loss of neurons in the globus pallidus and substantia nigra, probably as a result of the direct toxic effect of the metal. [ 4 ]

Carbon monoxide (CO). Parkinsonism can be caused by exposure to high levels of carbon monoxide. In one study of 242 patients with carbon monoxide (CO) poisoning examined between 1986 and 1996, parkinsonism was diagnosed in 23 (9.5%). [ 5 ] This variant of toxic parkinsonism is usually unresponsive to levodopa medications, which helps distinguish it from Parkinson's disease. The syndrome is based on the death of neurons in the striatum and globus pallidus. [ 6 ]

MPTP (neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Several drug addicts who injected intravenous meperidine laced with MPTP developed acute parkinsonian syndrome. This was subsequently reproduced in laboratory animals by injecting MPTP alone. MPTP is thought to be converted by MAO type B to an active metabolite, MPP+, which accumulates in dopaminergic terminals via the dopamine high-affinity transport system. In dopaminergic neurons, MPP+ is stored bound to neuromelanin. By slowly releasing it, it inhibits complex I of the mitochondrial electron transport chain, promoting excessive formation of free radicals that are toxic to neurons. Although MPP+ can inhibit complex I in other cells, they release it more quickly than dopaminergic neurons. [ 7 ]

PET scans of several asymptomatic individuals given MPTF showed a reduction in the number of dopaminergic terminals. Several of these individuals subsequently developed Parkinsonian symptoms, further supporting the idea that age-related neuronal loss may contribute to the disease.

Many studies have linked pesticide exposure to an increased risk of Parkinson's disease. [ 8 ] Other suggested risks include living in rural areas and certain occupations.

Smoking, caffeine, and nonsteroidal anti-inflammatory drug (NSAID) use appear to reduce the risk of PD, while a low-lipid, low-dairy diet, high calorie intake, and head injury may increase the risk.[ 9 ]

The increased risk of Parkinson's disease (PD) in men compared to women is well known; men are approximately twice as likely to develop the disease as women. Experimental data support a potential neuroprotective role for estrogens. [ 10 ], [ 11 ], [ 12 ]

An analysis of health data from more than 62 million people in the United States has found a link between having your appendix removed and an increased risk of developing Parkinson's disease. The study found that the likelihood of developing Parkinson's disease increased more than threefold after an appendectomy and was not affected by age, gender or race.

Genetic causes

There are several forms of Parkinson's disease, some of which (<5%) are monogenic, i.e. caused by mutations in individual genes. Currently, six genes have been identified for the clinically classical form of parkinsonism, including three autosomal dominant (SNCA, LRRK2, VPS35) and three autosomal recessive (Parkin, PINK1, DJ-1). In addition, there are many genes that cause atypical forms of parkinsonism. [ 13 ], [ 14 ], [ 15 ]

Pathogenesis of Parkinson's disease

The pathomorphological basis of Parkinson's disease is a decrease in the number of dopamine-producing neurons of the substantia nigra and, to a lesser extent, the ventral tegmentum. Before these neurons die, eosinophilic cytoplasmic inclusions called Lewy bodies are formed in them. The loss of more than 80% of pigmented dopaminergic neurons of the substantia nigra leads to a significant decrease in the number of presynaptic dopaminergic endings and, accordingly, dopamine reuptake zones and a decrease in the activity of tyrosine hydroxylase, as well as a decrease in the dopamine content in the putamen. To a lesser extent, the caudate nucleus, the nucleus accumbens, and the frontal cortex, which receive innervation mainly from the ventral tegmentum, are deprived of dopaminergic innervation. Levels of dopamine metabolites such as homovanillic acid or dihydroxyphenylacetate decrease to a lesser extent than dopamine itself, indicating increased dopamine turnover and increased activity of the remaining dopaminergic terminals. Postmortem studies have shown that the number of dopamine D1 and D2 receptors is increased in untreated patients with Parkinson's disease. However, no such changes are found in treated patients, either because of prolonged drug stimulation of these receptors or secondary changes in postsynaptic striatal neurons. [ 16 ]

Due to decreased dopamine release, B2-mediated striatal inhibition is weakened, leading to hyperactivity of the indirect pathway. At the same time, D1-mediated striatal stimulation is weakened, leading to decreased activity of the direct pathway. According to this model, patients with Parkinson's disease have difficulty performing tasks related to the implementation of sequential movements - due to decreased function of the direct pathway, and there is excessive inhibition of concomitant movements, leading to oligokinesia and bradykinesia - due to increased activity of the indirect pathway.

In Parkinson's disease, the number of noradrenergic neurons in the locus coeruleus decreases, and then noradrenergic endings in the anterior parts of the brain. In animals with experimental parkinsonism, an increased acetylcholine turnover in the brain was found, but these changes were not confirmed in studies of patients with parkinsonism. In patients with Parkinson's disease, muscarinic cholinergic receptor antagonists (anticholinergics) reduce the severity of symptoms, especially tremor.

In untreated laboratory animals with experimental parkinsonism, the number of GABA receptors in the external segment of the globus pallidus and its increase in the internal segment of the globus pallidus and substantia nigra were noted. These data are consistent with the assumptions of hyperactivity of the indirect pathway and hypoactivity of the direct pathway in Parkinson's disease. GABA receptor agonists may have a beneficial effect in Parkinson's disease by attenuating the stress-induced exacerbation of symptoms. In studies of the brain of patients with Parkinson's disease, decreased serotonin levels were noted, but there is no convincing evidence of a decrease in the number of neurons in the raphe nuclei. In patients with Parkinson's disease suffering from depression, the content of serotonergic markers in the cerebrospinal fluid is lower than in patients without depression. Therefore, antidepressants that act on the serotonergic system are often used to treat affective disorders in Parkinson's disease. [ 17 ]

High concentrations of enkephalin and dynorphin have been found in the striatum. The former is predominantly concentrated in GABAergic projection neurons of the indirect pathway, the latter in GABAergic neurons of the direct pathway. Although high concentrations of opioid and cannabinoid receptors have been found in the globus pallidus and substantia nigra, there have been virtually no studies of the efficacy of opioids and cannabinoids in Parkinsonism.

Although glutamate, substance P, neurotensin, somatostatin, cholecystokinin may also be involved in the pathogenesis of Parkinson's disease, there are currently no agents that selectively affect these systems. [ 18 ] From a theoretical point of view, inhibition of glutamatergic transmission in the corticostriatal or subthalamopallidal pathways may be effective in Parkinson's disease. However, clinical trials are currently underway to test this hypothesis. [ 19 ]

Selective susceptibility. The loss of dopaminergic neurons in Parkinson's disease may be due to several factors. First, there is the age-related decline in dopaminergic cell numbers. Both postmortem pathological studies and positron emission tomography data show that humans experience a natural loss of dopaminergic neurons and their terminals with age. This phenomenon, combined with genetic and environmental factors, may explain the increase in Parkinson's disease incidence with age. It is possible that some individuals are born with a lower number of dopaminergic neurons. Accordingly, it can be assumed that even as a result of normal aging, the number of neurons will fall below the threshold for the development of symptoms. In others, genetic factors are at work that accelerate the age-related loss of neurons. It has been noted that in patients who, in their youth, were exposed to certain toxins or infectious agents that reduce the number of dopaminergic neurons, symptoms may worsen with age, probably as a result of the “superimposition” of the process of age-related neuronal death. [ 20 ]

Only a small proportion of patients with Parkinson's disease have a familial nature, and the genetic defect can be inherited in an autosomal dominant manner or transmitted with the mitochondrial genome from the mother. In several families with an autosomal dominant type of inheritance of parkinsonism, a mutation in the alpha-synuclein gene was identified. It was subsequently discovered that alpha-synuclein is the main component of Lewy bodies. In this regard, it is assumed that the accumulation and pathological aggregation of alpha-synuclein may be a key factor leading to cell death through stimulation of the mechanisms of programmed cellular suicide (apoptosis). In this case, the accumulation of alpha-synuclein may be associated with genetically determined changes in its structure, post-translational pathological changes in its conformation, or dysfunction of the systems that prevent the accumulation of proteins in the cell and ensure their metabolic degradation. A significant proportion of patients with Parkinson's disease have mitochondrial dysfunction, which may contribute to increased formation of free radicals, a by-product of inefficient energy metabolism. The substantia nigra normally contains high concentrations of antioxidant substances (free radical scavengers) such as glutathione and catalase, but their levels in the brain are significantly reduced in Parkinson's disease. It is possible that an imbalance in the formation and neutralization of free radicals plays an important role in the pathogenesis of this disease. [ 21 ]

Exogenous factors. The influenza pandemic that broke out after World War I was accompanied by rare cases of Economo encephalitis. These patients developed an acute parkinsonian syndrome, which was often accompanied by additional manifestations such as oculogyric crises. In other patients, similar manifestations developed months or years after the acute phase of the disease. Pathological examination of the brain of patients with postencephalitic parkinsonism revealed neurofibrillary tangles in the substantia nigra, rather than the Lewy bodies characteristic of Parkinson's disease. It is believed that the causative agent of the disease was a virus that could penetrate the neurons of the substantia nigra and lead to their destruction, causing parkinsonism syndrome immediately or delayed. This virus was the cause of a significant number of cases of parkinsonism beginning in the 1930s. Subsequently, cases of parkinsonism caused by encephalitis of other etiologies were described. [ 22 ]