Aims

Despite numerous attempts to develop preclinical diagnosis of Parkinson’s disease (PD) based on searching premotor symptoms or biomarkers in body fluids, there is no technology recommended for clinical use. Indeed, all detected markers are not specific. This study aimed to develop a fundamentally new approach to preclinical diagnosis of PD based on a provocative test, which is widely used in internal medicine for diagnosis of chronic diseases.

Methods

MPTP was administered to mice for modeling preclinical stage of PD. In two weeks, mice received provocative agent – alpha-methyl-p-tyrosine (αMPT), a reversible inhibitor of tyrosine hydroxylase and dopamine synthesis.

Results

First, we used MPTP to model in mice preclinical PD with loss of striatal dopamine for 20% and 60%, but without motor disorders. Then, we selected a dose of αMPT, which causes the appearance of motor disorders in mice with minimal MPTP-induced loss of DA, but not in normal mice. This was due to a decrease of dopamine to 30%, the threshold for the onset of motor disorders in PD. Finally, we found the minimum doses of αMPT that, in mice with varying depletion of striatal dopamine, bring dopamine loss to a threshold at which motor disorders appear. This dose dependence can be used to estimate the degree of degradation of the nigrostriatal dopaminergic system in preclinical stage of PD.

Conclusions

This is the first attempt to develop a provocative test for preclinical diagnosis of PD, which can also be used to estimate the degradation of the nigrostriatal dopaminergic system.

Supported by Skolkovo Foundation.

Aims

Despite numerous attempts to develop preclinical diagnosis of Parkinson’s disease (PD) based on searching premotor symptoms or biomarkers in body fluids, there is no technology recommended for clinical use. Indeed, all detected markers are not specific. This study aimed to develop a fundamentally new approach to preclinical diagnosis of PD based on a provocative test, which is widely used in internal medicine for diagnosis of chronic diseases.

Methods

MPTP was administered to mice for modeling preclinical stage of PD. In two weeks, mice received provocative agent – alpha-methyl-p-tyrosine (αMPT), a reversible inhibitor of tyrosine hydroxylase and dopamine synthesis.

Results

First, we used MPTP to model in mice preclinical PD with loss of striatal dopamine for 20% and 60%, but without motor disorders. Then, we selected a dose of αMPT, which causes the appearance of motor disorders in mice with minimal MPTP-induced loss of DA, but not in normal mice. This was due to a decrease of dopamine to 30%, the threshold for the onset of motor disorders in PD. Finally, we found the minimum doses of αMPT that, in mice with varying depletion of striatal dopamine, bring dopamine loss to a threshold at which motor disorders appear. This dose dependence can be used to estimate the degree of degradation of the nigrostriatal dopaminergic system in preclinical stage of PD.

Conclusions

This is the first attempt to develop a provocative test for preclinical diagnosis of PD, which can also be used to estimate the degradation of the nigrostriatal dopaminergic system.

Supported by Skolkovo Foundation.