Dopamine transporter imaging is associated with long-term outcomes in Parkinson's disease

Biogen Idec, Cambridge, Massachusetts, USA. .
Movement Disorders (Impact Factor: 5.68). 09/2012; 27(11):1392-7. DOI: 10.1002/mds.25157
Source: PubMed


Dopamine (DA) transporter (DAT) imaging has been studied as a diagnostic tool for degenerative parkinsonism. Our aim was to measure the prognostic value of imaging for motor and nonmotor outcomes in Parkinson's disease (PD). We prospectively evaluated a Parkinson's cohort after enrollment in a de novo clinical trial with a battery of motor (UPDRS), cognitive (Montreal Cognitive Assessment), and behavioral measures. DAT imaging with [(123) I][β]-CIT and single-photon emission computerized tomography (SPECT) was performed at baseline and after 22 months. In total, 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan, consistent with PD, and were included in the analyses. The cohort was followed for 5.5 (0.8) years, with a mean duration of diagnosis of 6.3 (1.2). Lower striatal binding at baseline was independently associated with higher risk for clinical milestones and measures of disease severity, including motor-related disability, falling and postural instability, cognitive impairment, psychosis, and clinically important depressive symptoms. Subjects in the bottom quartile for striatal binding, compared to the top quartile, had an odds ratio (95% confidence interval) of 3.3 (1.7, 6.7) for cognitive impairment and 12.9 (2.6, 62.4) for psychosis. Change from baseline in imaging after 22 months was also independently associated with motor, cognitive, and behavioral outcomes. DAT imaging with [(123) I][β]-CIT and SPECT, shortly after the diagnosis of PD, was independently associated with clinically important long-term motor and nonmotor outcomes. These results should be treated as hypothesis generating and require confirmation. © 2012 Movement Disorder Society.

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    • "Chronic use of cocaine appears to lead to dysregulation of brain dopaminergic system (Hou et al. 2014). Several studies have shown that DA at high concentrations may participate in neurodegenerative processes, such as in Parkinson's disease (Ahlskog 2007; Ravina et al. 2012). Although cocaine is able to inhibit the reuptake of DA, noradrenaline and serotonin, its powerful effect is believed to ensue from its actions on the dopamine transporter (DAT) in neuron terminals, causing an increase of the concentration and of the intensity of action of DA at the postsynaptic receptors (Fig. 1) (Gowrishankar et al. 2014; Martin et al. 2011). "
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    ABSTRACT: Substance use disorder is an emerging problem concerning to human health, causing severe side effects, including neurotoxicity. The use of illegal drugs and the misuse of prescription or over-the-counter drugs are growing in this century, being one of the major public health problems. Ethanol and cocaine are one of the most frequently used drugs and, according to the National Institute on Drug Abuse, their concurrent consumption is one of the major causes for emergency hospital room visits. These molecules act in the brain through different mechanisms, altering the nervous system function. Researchers have focused the attention not just in the mechanism of action of these drugs, but also in the mechanism by which they damage the nervous tissue (neurotoxicity). Therefore, the goal of the present review is to provide a global perspective about the mechanisms of the neurotoxicity of cocaine and ethanol.
    Neurotoxicity Research 06/2015; 28(3). DOI:10.1007/s12640-015-9536-x · 3.54 Impact Factor
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    • "This is coherent with the view that DA terminals presenting more DAT show increased sensitivity to subsequent intoxication (Bannon, 2005). This needs further confirmation and if this is the case longitudinal monitoring of human patient populations presenting identified risks for the development of PD might be envisioned (Mossa et al., 2012; Ravina et al., 2012; Ziebell et al., 2012). "
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    ABSTRACT: The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BPND during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanism. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.
    NeuroImage 08/2014; 102. DOI:10.1016/j.neuroimage.2014.07.059 · 6.36 Impact Factor
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    • "[35] In addition, an association between dopaminergic imaging abnormalities and worse cognitive performance in PD with dementia (PDD) patients has been reported [36,37]. In longitudinal studies, both amyloid deposition and dopamine deficiency have been associated with the risk of cognitive decline in patients with PD. [38,39] Our study may have been particularly suited to identify an association between cognition and florbenazine imaging because of the large variance in both of these parameters in the DLB patients. For example, MMSE scores in our DLB patients ranged from 4–28. "
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    ABSTRACT: Biomarkers based on the underlying pathology of Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson's disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2). Patients with DLB and AD, Parkinson's disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism. 11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/ HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011). The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients ( identifier: NCT00857506, registered March 5, 2009).
    BMC Neurology 04/2014; 14(1):79. DOI:10.1186/1471-2377-14-79 · 2.04 Impact Factor
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