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

Abstract

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.

Long-Term Test–Retest Reliability of Striatal and Extrastriatal Dopamine D2/3 Receptor Binding: Study with [11C]Raclopride and High-Resolution PET

“…[9][10][11] Changes in extrastriatal [ 11 C]raclopride binding have also been associated with brain pathologies such as Parkinson's, Huntington's, and Alzheimer's diseases. [12][13][14] The loci of the extrastriatal reductions of [ 11 C]raclopride binding in the abovementioned studies are also consistent with the distribution of extrastriatal D 2/3 receptors reported in postmortem studies, where the thalamus has the highest density of D 2/3 receptors followed by the lateral temporal cortex, the anterior cingulate, and the frontal cortex. 15 The region of interest (ROI) measurement of striatal D 2/3 receptor binding using single-bolus [ 11 C]raclopride injection is highly reliable.…”

“…[9][10][11] Changes in extrastriatal [ 11 C]raclopride binding have also been associated with brain pathologic assesment, such as Parkinson's, Huntington's, and Alzheimer's diseases. [12][13][14] Moreover, a recent study using diffusion-weighted magnetic resonance imaging and PET found that connectivity-based subdivision of human striatum improved the evaluation of regional differences in DA transmission, supporting an association between striatal DA release and cortical connectivity. 35 36,37 In the current study, cortical VAR and ICC values were good to moderate, ranging from 6.1%, 0.79 (temporal cortex) to 13.1%, 0.67 (superior frontal gyrus).…”

Positron Emission Tomography in Diagnosis and Differential Diagnosis of Parkinson’s Disease

“…Since it is commonly accepted that motor symptoms appear earliest after 50% and more of nigrostriatal neurons are lost, PET techniques obviously are sensitive enough to pick up that loss at an earlier stage [40] . This is further supported by pathologic PET findings in asymptomatic subjects of examinations in twins, familial PD, parkin and other inherited PD kindreds [33,[41][42][43][44] .…”

“…PET imaging of presynaptic terminal functions, therefore, reveals reduced radioligand uptake in the striatum of PD patients with a more pronounced decrease in the (posterior) putamen than in the caudate, and usually shows an asymmetry with more severe affection of the striatum contralateral to the clinically more affected limbs [8][9][10][30][31][32] . This pattern has not only been reported in sporadic PD but also in juvenile, young-onset parkinsonism and patients with parkin gene mutations [33][34][35] . Generally, significant correlations between disease severity and disability stages with the extent of the reduction in presynaptic terminal measures have been reported [15,31,36,37] .…”

Nigrostriatal Dopamine Terminal Imaging with Dopamine Transporter SPECT: An Update

“…This pattern has been reported not only in sporadic PD but also in juvenile, young-onset parkinsonism and patients with parkin gene mutations. Whereas the latter notions were derived mainly from PET investigations, similar observations would have been obtained by the use of DAT SPECT ligands (19)(20)(21).…”