Young-Onset Parkinson Disease With and Without Parkin Gene Mutations

Thobois, Stéphane; Ribeiro, Maria-João; Lohmann, Ebba; Dürr, Alexandra; Pollak, Pierre; Rascol, Olivier; Guillouet, Stéphane; Chapoy, Elizabeth; Costes, Nicolas; Agid, Yves; Rémy, Philippe; Brice, Alexis; Broussolle, Emmanuel

doi:10.1001/archneur.60.5.713

Cited by 31 publications

(25 citation statements)

References 36 publications

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“…In both YOPD groups, the reduction of presynaptic markers of the dopaminergic system (i.e., 18 F-fluoro-L-DOPA and 11 C-PE2I) reveals a pattern that is in line with previous studies (9,13,16,(26)(27)(28). Indeed, there is a marked anteroposterior gradient, with all caudate-to-putamen ratios higher than 1.33, an observation similar to that made in sporadic PD.…”

Section: Discussionsupporting

confidence: 88%

“…This symmetric reduction fits well with the absence of significant clinical asymmetry of the motor signs at this stage of the disease, despite an asymmetry at disease onset. This symmetry, occasionally reported in previous studies (13), is present in both nonparkin and parkin patients, suggeting that the symmetry is related to the genetic origin of the disease in these groups. However, this question of symmetry or asymmetry has to be taken with caution because, at this stage of the disease, the dopaminergic cell loss is major and may reach a floor at which a much larger population would be needed before differences in tracer uptake between the 2 sides would become evident.…”

Section: Discussionsupporting

confidence: 78%

“…PET studies performed in carriers of parkin mutations have shown a marked reduction of striatal 18 F-fluoro-L-3,4-dihydroxyphenylalanine ( 18 F-fluoro-L-DOPA) uptake, which predominated in both putamen and seemed more symmetric than in sporadic disease (9)(10)(11)(12)(13)(14)(15). However, no correlation has been provided between motor or cognitive status of YOPD patients and the extent of dopaminergic lesions measured with functional imaging.…”

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confidence: 99%

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A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

Ribeiro

Thobois²,

Lohmann

et al. 2009

J Nucl Med

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The impact of parkin gene mutations on nigrostriatal dopaminergic degeneration is not well established. The purpose of this study was to characterize by PET using 18 F-fluoro-L-3,4-dihydroxyphenylalanine ( 18 F-fluoro-L-DOPA), 11 C-PE2I, and 11 C-raclopride the pattern of dopaminergic lesions in young-onset Parkinson disease (YOPD) patients with or without mutations of the parkin gene and to correlate the clinical and neuropsychologic characteristics of these patients with PET results. Methods: A total of 35 YOPD patients were enrolled (16 with parkin mutation, 19 without). The uptake constant (K i ) of 18 F-fluoro-L-DOPA and the binding potential (BP) of 11 C-PE2I (BP DAT ) and of 11 C-raclopride (BP D2 ) were calculated in the striatum. Comparisons were made between the 2 groups of YOPD and between controls and patients. For each radiotracer, parametric images were obtained, and statistical parametric mapping (SPM) analysis using a voxel-by-voxel statistical t test was performed. Correlations between the cognitive and motor status and PET results were analyzed. Results: In YOPD patients, 18 F-fluoro-L-DOPA K i values were reduced to 68% (caudate) and 40% (putamen) of normal values (P , 0.0001). This decrease was symmetric and comparable for nonparkin and parkin patients. No correlation was found between the K i values and cognitive or motor status. 11 C-PE2I BP DAT values in YOPD patients were decreased to 56% (caudate) and 41% (putamen) of normal values (P , 0.0001) and did not differ between the 2 YOPD populations. The mean 11 C-raclopride BP D2 values were reduced to 72% (caudate) and 84% (putamen) of the normal values (P , 0.02) and did not differ between nonparkin and parkin patients. SPM analyses showed in patients an additional decrease of 11 C-raclopride in the frontal cortex and a decrease of 18 F-fluoro-L-DOPA and 11 C-PE2I uptake in the substantia nigra bilaterally (P , 0.05, false-discovery rate-corrected). Conclusion: Carriers of parkin mutations are indistinguishable on PET markers of dopaminergic dysfunction from other YOPD patients with long disease duration.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

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A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

Ribeiro

Thobois²,

Lohmann

et al. 2009

J Nucl Med

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“…Several studies with fluorodopa and PET in parkin disease have been based on a small number of cases, and one report on a larger series was published recently [147]. These studies confirm the presence of presynaptic dopaminergic dysfunction, as in common PD.…”

Section: Neuroimaging Studiesmentioning

confidence: 80%

“…These studies confirm the presence of presynaptic dopaminergic dysfunction, as in common PD. Moreover, PET abnormalities in parkin patients display some degree of left-right asymmetry, perhaps less pronounced than in classical PD, and a clear rostro-caudal gradient (the putamen being more severely affected than caudate), as in classical PD [147]. Mild abnormalities were observed in asymptomatic heterozygous carriers, suggesting the presence of subclinical disease [135,136].…”

Section: Neuroimaging Studiesmentioning

confidence: 94%

Unraveling the pathogenesis of Parkinson?s disease ? the contribution of monogenic forms

Bonifati

Oostra

Heutink

2004

CMLS, Cell. Mol. Life Sci.

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The field of Parkinson's disease pathogenesis is rapidly evolving from the one of a monolithic and obscure entity into the one of a complex scenario with several known molecular players. The ongoing systematic exploration of the genome holds great promise for the identification of the genetic factors conferring susceptibility to the common non-Mendelian forms of this disease. However, most of the progress of the last 5 years has come from the successful mapping and cloning of genes responsible for rare Mendelian variants of Parkinson's disease. These discoveries are providing tremendous help in understanding the molecular mechanisms of this devastating disease. Here we review the genetics of the monogenic forms of Parkinson's disease. Moreover, we focus on the mechanisms of disease caused by alpha-synuclein and parkin mutations, and the implications of this growing body of knowledge for understanding the pathogenesis of the common forms of the disease.

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Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation inPSEN1With Familial Alzheimer Disease Among Caribbean Hispanics

et al. 2015

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IMPORTANCE The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures.OBJECTIVE To identify genetic variants that modify age at onset of AD. DESIGN, SETTING, AND PARTICIPANTS Using a subset of Caribbean Hispanic families that carry the PSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics. MAIN OUTCOMES AND MEASURES Age at onset of AD.RESULTS Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1.CONCLUSIONS AND RELEVANCE Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD.

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Young-Onset Parkinson Disease With and Without Parkin Gene Mutations

Abstract: The pattern of fluorodopa F 18 uptake in the striatum of YOPD patients is similar to that of patients with idiopathic Parkinson disease and does not depend on the presence or absence of mutations of the parkin gene.

Cited by 31 publications

References 36 publications

A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

Unraveling the pathogenesis of Parkinson?s disease ? the contribution of monogenic forms

Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation inPSEN1With Familial Alzheimer Disease Among Caribbean Hispanics

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