Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA. J Neural Transm

Department of Neurology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
Journal of Neural Transmission (Impact Factor: 2.87). 08/2008; 115(7):1001-9. DOI: 10.1007/s00702-008-0030-y
Source: PubMed

ABSTRACT Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

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Available from: Anna L Bartels, Aug 20, 2015
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    • "One of the first in vivo pieces of evidence was provided by Bartels and colleagues in an investigation of ABC transporter function in patients with neurodegenerative syndromes: PD, progressive supranuclear palsy (PSP), and multi-system atrophy (MSA), which are characterized by accumulation of aSyn or Tau (Bartels et al., 2008b). These disorders were examined by positron-emission tomography (PET) using an ABC transporter-specific probe, [ 11 C]verapamil , that is exported exclusively by ABCB1 (Bartels et al., 2008b). They demonstrated a specific accumulation of the radioprobe in brain regions where these diseases primarily start, e.g. "
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    • "Furthermore, Bartels et al. found an increase in the cerebral 11 C-verapamil distribution in ten patients with advanced PD treated with levodopa and dopaminergic agonists, in comparison to healthy controls [183] (Fig. 3A). On the other hand, these authors demonstrated that ten young de novo PD patients presented a decrease of cerebral 11 C-verapamil in the brain stem, indicating a localized upregulation or increased function of P-gp soon after the onset of PD [184] (Fig. 3B), suggesting a neuroprotective response in early stages (non-medicated) of PD. Of note, the results showing a decrease in P-gp functionality relative to PD progression do not confirm whether or not this is a consequence of the antiparkinsonian therapy. "
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    • "Expression of MDR1 in blood vessels is reduced in the striatum of PD patients compared to control subjects [212]. Additionally, studies that examined the uptake of [ 11 C]verapamil, a compound that is usually extruded from the brain by Pgp, demonstrate a significant elevation of [ 11 C]verapamil in PD patients compared to controls [213] [214], suggesting that Pgp dysfunction contributes to PD pathogenesis [213] [214]. Polymorphisms in MDRPs have also been examined as they relate to PD risk. "
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