Экономическая эффективность доклинической диагностики болезни Паркинсона: марковская модель

This article contains a pharmacoeconomic analysis of early (preclinical) diagnosis of Parkinson's disease in Russia. Previous works show that using a combination of socio-economic determinants and a panel of blood biomarkers one may distinguish a Parkinsonism-related “risk group” among the entire population. This group consists of people who are most vulnerable to parkinsonism or are already ill, but at the preclinical stage. Together with the approach traditionally used in the pharmacoeconomics of chronic and long-term diseases, based on the representation of the dynamics of the development of the disease using Markov chains - discrete random processes without memory - this makes it possible to analyze the economic effects of early detection of cases and conducting preventive preclinical therapy. The work investigates the Markov model of Parkinson's disease, consisting of nine states - five states corresponding to the stages HY1-HY5, two preclinical states ("risk group", "prodromal state"). We use as the initial data for the model the probability of transition between states and health-adjusted quality of life (HRQoL) estimates, published in a number of works of researchers affiliated with AbbVie Corporation, and calculate the cost of therapy based on open data on the cost of drugs and procedures in Russian market. Moreover, we show that due to the introduction of preclinical diagnostics and preventive treatment at preclinical stages, identified patients can significantly increase the average survival time (in quality-adjusted life-years) compared to standard therapy, and the average cost per patient until the end of life can be significantly reduced

Оценка эффективности доклинической диагностики болезни Паркинсона методом "затраты-полезность"

Neurodegenerative diseases, Parkinson disease being an example, set challenges to modern societies both in terms of premature deaths and resources spent on treatment of the diseases. Prevention and early diagnostics in particular, are potential directions towards higher economic efficiency of healthcare interventions in this area. We suggest a way to modify the cost-utility approach to evaluation of economic efficiency of an early diagnostics method of Parkinson disease (PD) at the laboratory stage of the diagnostics method. The lack of detailed understanding of the early testing group selection and composition are the major challenges to economic evaluation here. In particular, we consider the approach to diagnose PD at the prodromal stage suggested by Ugrumov 2020. The early diagnostics at the prodromal stage, accompanied by neuroprotective therapy of those identified at high risk of PD, allows postponing PD development for later years. The innovative approach implies saving both direct and indirect costs of PD treatment in comparison with traditional approach but adds costs of testing for the high risk of PD. The latter component may be non-trivial depending on the rules of selection into the group of tested. We suggest a way to modify the cost-utility evaluation procedure so that to take this uncertainty into account. We formulate the economic efficiency condition of the early diagnostics method in terms of the minimal probability of PD in the tested group and estimate the probability based on the Russian data. The latter sets the important threshold for innovative technology when moving from the laboratory into the clinical stage

Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons

Searching for Biomarkers in the Blood of Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

Parkinson’s disease (PD) is diagnosed many years after its onset, under a significant degradation of the nigrostriatal dopaminergic system, responsible for the regulation of motor function. This explains the low effectiveness of the treatment of patients. Therefore, one of the highest priorities in neurology is the development of the early (preclinical) diagnosis of PD. The aim of this study was to search for changes in the blood of patients at risk of developing PD, which are considered potential diagnostic biomarkers. Out of 1835 patients, 26 patients were included in the risk group and 20 patients in the control group. The primary criteria for inclusion in a risk group were the impairment of sleep behavior disorder and sense of smell, and the secondary criteria were neurological and mental disorders. In patients at risk and in controls, the composition of plasma and the expression of genes of interest in lymphocytes were assessed by 27 indicators. The main changes that we found in plasma include a decrease in the concentrations of l-3,4-dihydroxyphenylalanine (L-DOPA) and urates, as well as the expressions of some types of microRNA, and an increase in the total oxidative status. In turn, in the lymphocytes of patients at risk, an increase in the expression of the DA D3 receptor gene and the lymphocyte activation gene 3 (LAG3), as well as a decrease in the expression of the Protein deglycase DJ-1 gene (PARK7), were observed. The blood changes we found in patients at risk are considered candidates for diagnostic biomarkers at the prodromal stage of PD

Searching for Biomarkers in the Blood of Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

Parkinson’s disease (PD) is diagnosed many years after its onset, under a significant degradation of the nigrostriatal dopaminergic system, responsible for the regulation of motor function. This explains the low effectiveness of the treatment of patients. Therefore, one of the highest priorities in neurology is the development of the early (preclinical) diagnosis of PD. The aim of this study was to search for changes in the blood of patients at risk of developing PD, which are considered potential diagnostic biomarkers. Out of 1835 patients, 26 patients were included in the risk group and 20 patients in the control group. The primary criteria for inclusion in a risk group were the impairment of sleep behavior disorder and sense of smell, and the secondary criteria were neurological and mental disorders. In patients at risk and in controls, the composition of plasma and the expression of genes of interest in lymphocytes were assessed by 27 indicators. The main changes that we found in plasma include a decrease in the concentrations of l-3,4-dihydroxyphenylalanine (L-DOPA) and urates, as well as the expressions of some types of microRNA, and an increase in the total oxidative status. In turn, in the lymphocytes of patients at risk, an increase in the expression of the DA D3 receptor gene and the lymphocyte activation gene 3 (LAG3), as well as a decrease in the expression of the Protein deglycase DJ-1 gene (PARK7), were observed. The blood changes we found in patients at risk are considered candidates for diagnostic biomarkers at the prodromal stage of PD