No Differential Regulation of Dopamine Transporter (DAT) and Vesicular Monoamine Transporter 2 (VMAT2) Binding in a Primate Model of Parkinson Disease

Karimi, Morvarid; Loftin, Susan K.; Brown, Chris; Xia, Huchuan Cedric; Xu, Jinbin; Mach, Robert H.; Perlmutter, Joel S.

doi:10.1371/journal.pone.0031439

Cited by 30 publications

(55 citation statements)

References 49 publications

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“…9), and all striatal measures correlated strongly with each other; but note that these postmortem measures were done only 2 months after MPTP. 9,29 The consistency of all of the terminal field measures strongly supports that the relationship between terminal fields and nigral cell bodies does not reflect insensitivity of the striatal measures.…”

Section: Measurement Of Pd Severitymentioning

confidence: 63%

Neuroimaging biomarkers for Parkinson disease: Facts and fantasy

Perlmutter¹,

Norris

2014

Annals of Neurology

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In this grand rounds, we focus on development, validation, and application of neuroimaging biomarkers for Parkinson disease (PD). We cover whether such biomarkers can be used to identify presymptomatic individuals (probably yes), provide a measure of PD severity (in a limited fashion, but frequently done poorly), investigate pathophysiology of parkinsonian disorders (yes, if done carefully), play a role in differential diagnosis of parkinsonism (not well), and investigate pathology underlying cognitive impairment (yes, in conjunction with postmortem data). Along the way, we clarify several issues about definitions of biomarkers and surrogate endpoints. The goal of this lecture is to provide a basis for interpreting current literature and newly proposed clinical tools in PD. In the end, one should be able to critically distinguish fact from fantasy. Ann Neurol 2014;76:769–783

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Section: Measurement Of Pd Severitymentioning

confidence: 63%

Neuroimaging biomarkers for Parkinson disease: Facts and fantasy

Perlmutter¹,

Norris

2014

Annals of Neurology

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“…All 16 monkeys completed the study and demonstrated a wide range of severity of parkinsonism from none in controls to severe unilateral parkinsonism with the highest doses of MPTP (Tabbal et al, 2012). All routine animal care procedures were described in detail (Tian et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

“…Detailed descriptions of the approaches have been published earlier (Brown et al, 2012; Karimi et al, 2013; Tabbal et al, 2012; Tian et al, 2012). The following is a short overview.…”

Section: Methodsmentioning

confidence: 99%

“…These newly measured variables were compared with previously published data from the same animals of in vivo PET, quantified autoradiography, striatal dopamine, nigral cell counts and motor ratings of parkinsonism (Brown et al, 2012; Karimi et al, 2013; Tabbal et al, 2012; Tian et al, 2012). This allows us to investigate whether the measures of axonal fibers fall in between the striatal terminal field and nigral cell body measures in relative to motor parkinsonism.…”

Section: Introductionmentioning

confidence: 99%

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In vivo measures of nigrostriatal neuronal response to unilateral MPTP treatment

et al. 2014

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A single unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into non-human primates causes injury to the nigrostriatal pathway including nigral cell bodies, axons and striatal terminal fields. In this model, motor parkinsonism correlates well with the loss of nigral dopaminergic cell bodies but only correlates with in vitro measures of nigrostriatal terminal fields when nigral cell loss does not exceed 50%. The goals of this study are to determine the relationship of motor parkinsonism with the degree of injury to nigrostriatal axons, as reflected by in vitro fiber length density measures, and compare in vivo with in vitro measures of striatal terminal fields. We determined axon integrity by measuring fiber length density with tyrosine hydroxylase (TH) immunohistology and dopamine transporter (DAT) density with DAT immunohistology. We then calculated the terminal arbor size and compared these measures with previously published data of quantified in vivo positron emission tomography (PET) measures of presynaptic dopaminergic neurons, autoradiographic measures of DAT and vesicular monoamine transporter type 2 (VMAT2), striatal dopamine, nigral cell counts, and parkinsonian motor ratings in the same animals. Our data demonstrate that in vivo and in vitro measures of striatal terminal fields correlate with each other regardless of the method of measurement. PET-based in vivo striatal measures accurately reflect in vitro measures of DAT and VMAT2. Terminal arbor size and other terminal field measures correlate with nigral TH immunoreactive (TH-ir) cell counts only when nigral TH-ir cell loss does not exceed 50%. Fiber length density was the only striatal measure that linearly correlated with motor ratings (Spearman: r = −0.81, p < 0.001, n = 16).

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“…Striatal dopamine was measured in the tissue extracts using high performance liquid chromatography with electrochemical detection (HPLC-EC) (Karimi et al, 2006; Tian et al, 2012). The analytical data were expressed as ng/g of brain tissue.…”

Section: Methodsmentioning

confidence: 99%

Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates

Dugan

Tian

Quick

et al. 2014

Annals of Neurology

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Objective We evaluated the efficacy of the potent antioxidant C3 to salvage nigrostriatal neuronal function after MPTP exposure in nonhuman primates. C3 is a first-in-class functionalized water-soluble fullerene which reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3 has not been evaluated as a neuroprotective agent in a Parkinson model in vivo. Methods Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTP-lesioned primates were given systemic C3 (n = 8) or placebo (n = 7) for two months starting one week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated non-human primate rating scale, kinematic analyses of peak upper extremity velocity, PET imaging of 6-[18F]fluorodopa (FD, reflects dopa decarboxylase) and [11C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), as well as ex vivo quantification of striatal dopamine (DA) and stereologic counts of tyrosine hydroxylase (TH) immunostained neurons in substantia nigra. Results After two months, C3 treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3 treated animals developed any toxicity. Interpretation Systemic treatment with C3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3 as a promising therapeutic agent for PD.

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No Differential Regulation of Dopamine Transporter (DAT) and Vesicular Monoamine Transporter 2 (VMAT2) Binding in a Primate Model of Parkinson Disease

Cited by 30 publications

References 49 publications

Neuroimaging biomarkers for Parkinson disease: Facts and fantasy

Neuroimaging biomarkers for Parkinson disease: Facts and fantasy

In vivo measures of nigrostriatal neuronal response to unilateral MPTP treatment

Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates

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