The blood-brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates--evidence from in vivo neuroimaging studies

Abstract

It has been suggested, based on rodent studies, that levodopa (L-dopa) induced dyskinesia is associated with a disrupted blood-brain barrier (BBB). We have investigated BBB integrity with in vivo neuroimaging techniques in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primates exhibiting L-dopa-induced dyskinesia. Magnetic resonance imaging (MRI) performed before and after injection of Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) revealed an intact BBB in the basal ganglia showing that l-dopa-induced dyskinesia is not associated with a disrupted BBB in this model.

Figure 1. The BBB of the basal ganglia is intact as shown by Gadolinium-DTPA (Gd-DTPA) MRI studies in dyskinetic monkeys

T1 weighted axial brain MRI images before (upper panel) and after (lower panel) peripheral injection of Gadolinium-DTPA, 0.3 mmol/kg to a dyskinetic macaque. Post Gd-DTPA there is marked signal enhancement of the hypothalamic/pituitary region, structures lacking a BBB, and the sagittal sinus, but no signal enhancement of the basal ganglia, including the putamen, caudate, globus pallidus and substantia nigra is observed. Put=putamen; Cd=Caudate nucleus; GPe=Globus pallidus externa, GPi=Globus pallidus interna SN=Substantia nigra, Pit/Hyp=Pituitary/hypothalamic region. L=Left; R=Right. Bright spots near SN are contrast filled blood vessels.

Figure 2. Quantitative results following injection of Gadolinium-DTPA in dyskinetic monkeys show an intact BBB of the basal ganglia

(A) Averaged plot across all animals showing the effects of 0.3 mmol/kg Gd-DTPA as a function of time using serial gradient echo imaging with flip angle alpha and short TE (TR/TE = 235/4.5ms) with 30s temporal resolution. Injections were made during serial imaging for comparison effects are shown in the sagittal sinus vein (Sag sinus), the pituitary/hypothalamic region (Pit/Hyp) and the substantia nigra (SN). There is no increase in the SN aside from a small contribution attributable to the intrinsic blood volume. (B) Bar plot showing the averages across all animals for signal enhancement at an average of 16 min after GD-DTPA injection using a high resolution (0.65 mm isotropic) T1-weighted sequence (TR/TI/TE = 1910/1100/3.1 ms). The regions shown are the same as in (A) but also include putamen (Put), caudate (Cd), jaw muscle (muscle), and occipital cortex (Occ Cx) as a control gray matter region. One way ANOVA across brain regions showed that there were no significant differences between images of the Cd, Put, SN or OccCx with either the gradient echo data in (A) (F23,3 = 1.27; p >0.3) or in (B) (F23,3 = 1.40; p > 0.25). As expected, there were highly significant differences between the latter four regions and either muscle, pit/hyp or sagittal sinus.