Perspective: Identification of genetic variants associated with dopaminergic compensatory mechanisms in early Parkinson's disease

Lior Greenbaum,Mordechai Lorberboym,Yoav Kohn,Alexander Khlebtovsky,Ruth Djaldetti,Eldad Melamed,Yael Barhum,Bernard Lerer,Amihai Rigbi

doi:10.3389/fnins.2013.00052

Lior Greenbaum, Mordechai Lorberboym + Show 7 more

Open Access

https://doi.org/10.3389/fnins.2013.00052

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Abstract

Parkinson's disease (PD) is slowly progressive, and heterogeneity of its severity among individuals may be due to endogenous mechanisms that counterbalance the striatal dopamine loss. In this perspective paper, we introduce a neuroimaging-genetic approach to identify genetic variants, which may contribute to this compensation. First, we briefly review current known potential compensatory mechanisms for premotor and early disease PD, located in the striatum and other brain regions. Then, we claim that a mismatch between mild symptomatic disease, manifested by low motor score on the Unified PD Rating Scale (UPDRS), and extensive Nigro-Striatal (NS) degeneration, manifested by reduced uptake of [123I]FP-CIT, is indicative of compensatory processes. If genetic variants are associated with the severity of motor symptoms, while the level of striatal terminals degeneration measured by ligand uptake is taken into account and controlled in the analysis, then these variants may be involved in functional compensatory mechanisms for striatal dopamine deficit. To demonstrate feasibility of this approach, we performed a small “proof of concept” study (candidate gene design) in a sample of 28 Jewish PD patients, and preliminary results are presented.

Highlights

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra, causing depletion in striatal dopamine level, variable clinical expressions, and a slowly deteriorating course (Dauer and Przedborski, 2003; Obeso et al, 2010)
There is an association between disease severity and disease duration, but the rate of disease progression is variable among patients
The inter-individual difference in severity of motor symptoms during early and mid duration of PD may be attributed to existence or lack of compensatory mechanisms for dopamine loss (Obeso et al, 2004)

Summary

INTRODUCTION

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra, causing depletion in striatal dopamine level, variable clinical expressions, and a slowly deteriorating course (Dauer and Przedborski, 2003; Obeso et al, 2010). It is plausible that compensatory mechanisms play a role in the motor symptomatic period, manipulating disease severity and progression (Brotchie and Fitzer-Attas, 2009). These functional mechanisms may counterbalance dopamine loss in early PD, attenuating the severity and progression of motor symptoms (Biju and de la Fuente-Fernández, 2009). Genetic variations probably predispose some individuals to better compensatory potential for the striatal dopamine loss We believe that this type of systematic research will offer initial tools required to identify these variants, and to trace genes that may be involved in compensatory mechanisms. The small sample size used in this report is underpowered, but the goal in this context is to present the new method and its possible applicability, and not to reach definitive conclusions

Identification of PD compensatory mechanisms

Findings

Absorption level in contralateral putamen