Dopamine Neuron Challenge Test for early detection of Parkinson\u2019s disease

Jingheng Zhou,Guohong Cui,Jicheng Li,Nicholas P Kobzar,Amy B Papaneri

doi:10.1038/s41531-021-00261-z

Jingheng Zhou, Guohong Cui + Show 3 more

Open Access

https://doi.org/10.1038/s41531-021-00261-z

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Abstract

Diagnosing Parkinson’s disease (PD) before the clinical onset proves difficult because the hallmark PD symptoms do not manifest until more than 60% of dopamine neurons in the substantia nigra pars compacta have been lost. Here we show that, by evoking a transient dopamine release and subsequently measuring the levels of dopamine metabolites in the cerebrospinal fluid and plasma, a hypodopaminergic state can be revealed when less than 30% of dopamine neurons are lost in mouse PD models. These findings may lead to sensitive and practical screening and diagnostic tests for detecting early PD in the high-risk population.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most common movement disorder, affecting 1% of the population over the age of 601,2
The hallmark pathological feature of PD is the progressive loss of dopamine (DA)-producing neurons (DANs) in the substantia nigra pars compacta (SNc), resulting in a cohort of motor deficits that worsen over time[3]
We measured the fluorescence change of dLight1.1 induced by intraperitoneal (i.p.) injections of 1) amphetamine, which acts on DA transporter (DAT) and releases DA13; 2) methylphenidate, which acts on DAT and blocks the reuptake of DA14; 3) D2R antagonist haloperidol, which increases the firing rate of DANs and DA release by blocking presynaptic D2Rs15, and 4) the combination of methylphenidate and haloperidol, which stimulates DA release and blocks DA reuptake at the same time

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most common movement disorder, affecting 1% of the population over the age of 601,2. The hallmark pathological feature of PD is the progressive loss of dopamine (DA)-producing neurons (DANs) in the substantia nigra pars compacta (SNc), resulting in a cohort of motor deficits that worsen over time[3]. Since PD motor symptoms typically do not manifest until more than 60% of SNc DANs have been lost[5,6,7], detection of the early-stage PD before the clinical onset is challenging. Though some success has been reported using neuroimaging methods, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT)-based DaTscan, to target DA transporter (DAT), these methods typically involve radiolabeled ligands and are not practical for general screening in the high-risk population[8]. The goal of this study is to develop a sensitive and practical laboratory test that can detect PD at an early stage

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