Parkinson's disease-related modulation of functional connectivity associated with the striatum in the resting state in a nonhuman primate model
ABSTRACT The goal of this study was to describe Parkinson's disease (PD)-related modulation of functional connectivity (FC) associated with the striatum in the resting state in a nonhuman primate model of early-stage PD. Weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (0.5 mg/kg body weight) were performed until parkinsonian motor symptoms developed in four macaques. After 13 weeks of MPTP treatment, all monkeys displayed parkinsonian symptoms. During the course of the experiment, each animal underwent four magnetic resonance imaging scans and four positron emission tomography (PET) scans with the vesicular monoamine transporter 2 (VMAT2)-selective ligand 9-[18F] fluoropropyl-(+)-dihydrotetrabenazine, performed prior to the beginning of MPTP administration as well as after 4, 9, and 13 MPTP injections. The FC profile of the striatum was evaluated using a seed voxel correlation approach and post hoc region of interest analysis on resting-state functional magnetic resonance imaging data. The PET images were subjected to region of interest analysis to examine brain regional reductions in VMAT2 density in the PD model. Significant reductions in the connectivity pattern of the striatal regions were observed: limbic striatum and left hippocampus; caudate nucleus/associative and brain regions, including the right pre-supplementary motor area and bilateral dorsolateral prefrontal cortex; putamen/associative region and left inferior temporal gyrus or right orbital and medial prefrontal cortex; and putamen/motor and cortical structures, including the right superior temporal gyrus and bilateral postcentral gyrus. Subsequent PET studies showed the progressive loss of striatal VMAT2 in the striatum with the presentation of parkinsonism. Significant differences between the specific uptake ratio reductions in each striatal subdivision were not found. By using a long-term, low-dose MPTP-lesioned nonhuman primate model, this study demonstrated PD-related decreased corticostriatal FC in a resting state; moreover, altered sensorimotor integration was also found in early-stage PD.
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ABSTRACT: [¹⁸F]AV-133 is a novel PET tracer for targeting the vesicular monoamine transporter 2 (VMAT2). The aim of this study is to characterize and quantify the loss of monoamine neurons with [¹⁸F]AV-133 in the MPTP-lesioned PD mouse model using animal PET imaging and ex vivo quantitative autoradiography (QARG). Optimal imaging time window of [¹⁸F]AV-133 was first determined in normal C57BL/6 mice (n = 3) with a 90-min dynamic scan. The reproducibility of [¹⁸F]AV-133 PET imaging was evaluated by performing a test-retest study within 1 week for the normal group (n = 6). For MPTP-lesioned studies, normal, and MPTP-treated [25 mg mg/kg once (Group A) and twice (Group B), respectively, daily for 5 days, i.p., groups of four normal and MPTP-treated] mice were used. PET imaging studies at baseline and at Day 4 post-MPTP injections were performed at the optimal time window after injection of 11.1 MBq [¹⁸F]AV-133. Specific uptake ratio (SUr) of [¹⁸F]AV-133 was calculated by [(target uptake-cerebellar uptake)/cerebellar uptake] with cerebellum as the reference region. Ex vitro QARG and immunohistochemistry (IHC) studies with tyrosine hydroxylase antibody were carried out to confirm the abundance of dopaminergic neurons. The variability between [¹⁸F]AV-133 test-retest striatal SUr was 6.60 ± 3.61% with less than 5% standard deviation between animals (intervariability). The percentages of MPTP lesions were Group A 0.94 ± 0.29, -42.1% and Group B 0.65 ± 0.09, -60.4%. By QARG, specific binding of [¹⁸F]AV-133 was reduced relative to the control groups by 50.6% and 60.7% in striatum and by 30.6% and 46.4% in substantia nigra (Groups A and B, respectively). Relatively small [¹⁸F]AV-133 SUr decline was noted in the serotonin and norepinephrine-enriched regions (7.9% and 9.4% in mid-brain). Results obtained from IHC consistently confirmed the sensitivity and selectivity of dopaminergic neuron loss after MPTP treatment. [¹⁸F]AV-133 PET SUr displayed a high test-retest stability. The SUr significantly declined in the caudate putamen but not in the hypothalamus and midbrain regions after MPTP treatment in the mouse brain. The results obtained for QARG and IHC were consistent and correlated well with the PET imaging studies. On the basis of these concordant results, we find that [¹⁸F]AV-133 should serve as a useful and reliable PET tracer for evaluating nigrostriatal degeneration.Synapse 09/2012; 66(9):823-31. DOI:10.1002/syn.21572 · 2.43 Impact Factor
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ABSTRACT: Although Parkinson's disease (PD) is traditionally considered a motor output disorder, recent evidence suggests that people with PD may have sensory and perceptual impairments that may underlie movement impairments. Yet there has not been any direct testing of perceptual judgments, especially when manipulating the sensory feedback on which these judgments are made. The present study investigated how perception might be influenced by sensory feedback to contribute to height estimations and obstacle stepping in PD relative to healthy age-matched control participants. Perceptual judgment accuracy was evaluated by judging 3 typically encountered obstacle heights in 2 sensory feedback conditions: (1) vision of foot available and (2) without vision of foot (reliance on proprioceptive feedback to estimate height). Then participants proceeded to walk and step over the obstacle. Fifteen individuals with PD and 15 healthy control participants completed the task. As seen with toe elevation, toe elevation variability, and toe error measures, individuals with PD overestimated the obstacle height and were significantly more variable when relying solely on proprioception (in contrast to when vision was available) compared with healthy controls, although no differences between groups in obstacle crossing were found. These results support the notion that sensory deficits may contribute to inaccuracy of perceptual judgment and has the potential to contribute to gait behaviors such as tripping and falling, especially when vision is not available. Future studies should carefully consider the impact of sensory and perceptual deficits that might contribute to movement planning problems and consequentially movement impairments.Movement Disorders 03/2012; 27(3):387-92. DOI:10.1002/mds.24042 · 5.63 Impact Factor
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ABSTRACT: By tracing radioactively labeled proteins transported by axonal flow, projections from area 4 to the ipsi- and contralateral neostriatum and claustrum were demonstrated in 7 monkeys. A reversed topographic organization was found on both sides for the corticoneostriatal and corticoclaustral projections. The most extensive terminal field could be observed in the putamen. In contrast, very few area 4 efferents seemed to terminate in the caudate nucleus. This suggests differential functions for the two striatal components in sensorimotor mechanisms. These unexpected results give further evidence for the superior sensitivity of the autoradiographic technique, although the limitations of the new method in delineating the injection field were noted.Brain Research 06/1975; 88(2):195-209. DOI:10.1016/0006-8993(75)90384-4 · 2.83 Impact Factor