Inter-hemispheric asymmetry of nigrostriatal dopaminergic lesion: a possible compensatory mechanism in Parkinson’s disease

Javier Blesa

doi:10.3389/fnsys.2011.00092

Abstract

The onset of Parkinson’s disease (PD) is characterized by focal motor features in one body part, which are usually correlated with greater dopaminergic depletion in the contralateral posterior putamen. The role of dopamine (DA) hemispheric differences in the onset and progression of motor symptoms of PD, however, remains undefined. Previous studies have demonstrated that unilateral manipulations of one nigrostriatal system affect contralateral DA turnover, indicating a functional and compensatory inter-dependence of the two nigrostriatal systems. In preliminary data obtained by our group from asymmetric PD patients, a higher asymmetry index as measured by 6-[18F]fluoro-L-dopa (18 F-DOPA) positron emission tomography (PET) was associated with a higher threshold (i.e., greater dopaminergic loss) for the onset of motor symptoms in the less-affected side. To further elucidate the underlying basis for this, we carried out a complementary study in monkeys using PET to assess and correlate the degree of dopaminergic striatal depletion with motor activity. Control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys with symmetrical lesions were characterized behaviorally and with 18F-DOPA PET. In parallel, an acute lesion was inflicted in the nigrostriatal projection unilaterally in one monkey, generating a 30% dopaminergic depletion in the ipsilateral striatum, which was not associated with any noticeable parkinsonian feature or deficit. The monkey remained asymptomatic for several months. Subsequently, this monkey received systemic MPTP, following which motor behavior and PET were repeatedly evaluated during progression of parkinsonian signs. The brains of all monkeys were processed using immunohistochemical methods. Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum. Although this work is still preliminary, the study agrees with our general hypothesis of hemispheric inter-dependence in the compensation of striatal DA deficit in PD.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized mainly by neuronal cell loss predominantly affecting the nigrostriatal dopaminergic pathway (Dickson et al, 2009)
Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum
Initial motor manifestations typically appear when about 70–80% of striatal nerve terminals and 50–60% of substantia nigra pars compacta (SNc) neurons have been lost (Bernheimer et al, 1973; Fearnley and Lees, 1990, 1991). Such a large reduction is associated with very mild clinical manifestations confined to a body segment, i.e., slowness of one hand, tremor of the foot, shoulder rigidity, etc., which is paralleled by unequal striatal innervation and asymmetric dopaminergic neuronal loss (Fearnley and Lees, 1991)

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized mainly by neuronal cell loss predominantly affecting the nigrostriatal dopaminergic pathway (Dickson et al, 2009). Initial motor manifestations typically appear when about 70–80% of striatal nerve terminals and 50–60% of substantia nigra pars compacta (SNc) neurons have been lost (Bernheimer et al, 1973; Fearnley and Lees, 1990, 1991). Such a large reduction is associated with very mild clinical manifestations confined to a body segment, i.e., slowness of one hand, tremor of the foot, shoulder rigidity, etc., which is paralleled by unequal striatal innervation and asymmetric dopaminergic neuronal loss (Fearnley and Lees, 1991)

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Conclusion