Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease.

Department of Radiology, Division of Nuclear Medicine, The University of Michigan Medical School, Ann Arbor, 48109-0028, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.34). 10/2006; 26(9):1198-212. DOI: 10.1038/sj.jcbfm.9600276
Source: PubMed

ABSTRACT The type-2 vesicular monoamine transporter (VMAT2) might serve as an objective biomarker of Parkinson disease (PD) severity. Thirty-one subjects with early-stage PD and 75 normal subjects underwent continuous intravenous infusion of (+)-[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography (PET) imaging to estimate the striatal VMAT2 binding site density with equilibrium tracer modeling. Parkinson disease patients were evaluated clinically in the practically defined 'off' state with the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr Scale (HY), and the Schwab and England Activities of Daily Living Scale (SE). In normal subjects there was age-related decline in striatal DTBZ binding, approximating 0.5% per year. In PD subjects, specific DTBZ binding was reduced in the caudate nucleus (CD; -44%), anterior putamen (-68%), and posterior putamen (PP; -77%). The PP-to-CD ratio of binding was reduced significantly in PD subjects. Dihydrotetrabenazine binding was also reduced by approximately 50% in the PD substantia nigra. Striatal binding reductions correlated significantly with PD duration and SE scores, but not with HY stage or with UPDRS motor subscale (UPDRS(III)) scores. Striatal and midbrain DTBZ binding was asymmetric in PD subjects, with greatest reductions contralateral to the most clinically affected limbs. There was significant correlation between asymmetry of DTBZ binding and clinical asymmetry measured with the UPDRS(III). In HY stage 1 and 1.5 subjects (n=16), PP DTBZ binding contralateral to the clinically unaffected body side was reduced by 73%, indicating substantial preclinical nigrostriatal pathology in PD. We conclude that (+)-[(11)C]DTBZ-PET imaging displays many properties necessary of a PD biomarker.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Consistent with postmortem data, in a recent positron emission tomography (PET) study, we demonstrated less [11C]-(+)-α-dihydrotetrabenazine (DTBZ) binding to striatal vesicular monoamine transporter, type 2 (VMAT2) in cocaine abusers compared to controls. A major limitation of these between-group comparison human studies is their inability to establish a causal relationship between cocaine abuse and lower VMAT2. Furthermore, studies in rodents that evaluated VMAT2 binding before and after cocaine self-administration do not support a reduction in VMAT2. Methods To clarify these discrepant VMAT2 findings and attribute VMAT2 reduction to cocaine abuse, we imaged four rhesus monkeys with [11C]DTBZ PET before and after 16-months of cocaine self-administration. [11C]DTBZ binding potential (BPND) in the striatum was derived using the simplified reference tissue method with the occipital cortex time activity curve as an input function. Results Chronic cocaine self-administration led to a significant (25.8 ± 7.8%) reduction in [11C]DTBZ BPND. Conclusions In contrast to the cocaine rodent investigations that do not support alterations in VMAT2, these results in nonhuman primates clearly demonstrate a reduction in VMAT2 binding following prolonged exposure to cocaine. Lower VMAT2 implies that fewer dopamine storage vesicles are available in the pre-synaptic terminals for release, a likely factor contributing to decreased dopamine transmission in cocaine dependence. Future studies should attempt to clarify the clinical significance of lower VMAT2 in cocaine abusers, for example, its relationship to relapse and vulnerability to mood disorders.
    Biological Psychiatry 06/2014; DOI:10.1016/j.biopsych.2014.06.012 · 9.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. Methods Presynaptic PET tracers 6-[18F]-fluorodopa (FD), [11C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [11C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration. ResultsWe found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R2 = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = −0.77, −0.71, respectively, p < 0.001), but FD uptake did not. InterpretationOur findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function. Ann Neurol 2013;74:602–610
    Annals of Neurology 10/2013; 74(4). DOI:10.1002/ana.23939 · 11.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task-related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel-based morphometry (VBM) on T1-weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp.
    Human Brain Mapping 03/2015; DOI:10.1002/hbm.22694 · 6.92 Impact Factor

Full-text (2 Sources)

Available from
Jun 10, 2014