Аннотация:The Parkinson’s disease (PD) is a progressive long-term neurodegenerative disorder that mainly affects the motor system (leads to tremors and difficulty with walking, movement, and coordination). The key component of PD is metabolic disturbance of dopamine (DA) involved in process of neuronal death. The distinguishing feature of the disease is that it remains asymptomatic for a long time, supposedly, due to the activation of neuroplasticity mechanisms. The appearance of the PD symptoms with the time is connected not only with the significant degradation of nigrostriatal system but with practically complete exhaustion of compensatory reserves in brain. According to the World Health Organization (WHO) more than 4 million people suffer from PD. In Russia there are up to 338 thousand patients with PD, the prevalence varies from 55 to 196 per 100 thousand of population.
The prognosis is unfavorable – PD is steadily progressing. At the same time, the number of cases and the number of patients at the age from 30 to 40 years is increasing. At the moment there is no method which could stop or slow down the development of neuronal degeneration. The only therapy is injecting dopamine precursor L-DOPA or dopamine agonists into blood in order to facilitate motor symptoms. But as the disease evolves it is necessary to increase the dose of drug, but it has toxic effect. In this situation it becomes obvious that the development of preclinical diagnostics and preventive treatment is required in order to at least slow down the neurodegenerative process. If the period of neuronal death below the threshold level, after which the motor symptoms manifest, could be extended for many years, a significant portion of patients would not experience discomfort almost by the natural end of life.
On the other hand, even the neuroprotective approach is ineffective at the early clinical stage as the most DA neurons are died. Hence it becomes obvious that this approach makes sense when the pool of DA neurons is practically full. This happens at a preclinical stage of PD which diagnostics has not been developed yet. In the literature it was shown that non-motor symptoms, including cognitive disorders, appear at preclinical stage preceding motor symptoms. Cognitive disorders could indicate the developing neurodegenerative process and become a way of early diagnostics of PD.
Research on non-motor symptoms of PD has predominantly focused on fronto-striatal functions. However, dopamine pathways ascending from the ventral tegmental area also innervate hippocampal structures and modulate hippocampal-dependent functions, such as spatial memory. This approach may limit understanding of the pathogenesis of PD. Cognitive symptoms are required to elucidate the exact mechanisms. Identifying the relative contributions of these pathways in PD patients with overlapping motor and cognitive symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.
Because of the impossibility of studying endogenous processes in human brain at preclinical stage, adequate animal models of PD are required. The model must meet the certain criteria. The most adequate model is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in mice. It reproduces the most part of symptoms. In our laboratory there were developed MPTP models of preclinical and clinical stages of PD. However, it is unclear whether the models reproduce the natural pathogenesis of the disease: firstly, the appearance of cognitive disorders and then the development of motor symptoms. If the models are adequate, they could be used for search of peripheral biochemical markers of the preclinical stage of PD.
