Pharmacologic MRI (phMRI) as a tool to differentiate Parkinson's disease-related from age-related changes in basal ganglia function

Abstract

The prevalence of both parkinsonian signs and Parkinson's disease (PD) per se increases with age. Although the pathophysiology of PD has been studied extensively, less is known about the functional changes taking place in the basal ganglia circuitry with age. To specifically address this issue, 3 groups of rhesus macaques were studied: normal middle-aged animals (used as controls), middle-aged animals with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, and aged animals (>20 years old) with declines in motor function. All animals underwent the same behavioral and pharmacologic magnetic resonance imaging (phMRI) procedures to measure changes in basal ganglia function in response to dopaminergic drug challenges consisting of apomorphine administration followed by either a D1 (SCH23390) or a D2 (raclopride) receptor antagonist. Significant functional changes were predominantly seen in the external segment of the globus pallidus (GPe) in aged animals and in the striatum (caudate nucleus and putamen) in MPTP-lesioned animals. Despite significant differences seen in the putamen and GPe between MPTP-lesioned versus aged animals, a similar response profile to dopaminergic stimulations was found between these 2 groups in the internal segment of the GP. In contrast, the pharmacologic responses seen in the control animals were much milder compared with the other 2 groups in all the examined areas. Our phMRI findings in MPTP-lesioned parkinsonian and aged animals suggest that changes in basal ganglia function in the elderly may differ from those seen in parkinsonian patients and that phMRI could be used to distinguish PD from other age-associated functional alterations in the brain.

Keywords: Aging; Apomorphine; MPTP; Parkinsonism; Pharmacologic MRI; Raclopride; SCH23390.

Figure 1

Ratings of parkinsonian features of motor dysfunction in MPTP-treated and aged animals. Normal control animals have a rating of zero on all features. ***P<0.001 MPTP vs aged animals.

Figure 2

phMR responses in the putamen. (2A) Similar pharmacological actions were found in responses to either APO or the subsequent administration of SCH between MPTP-treated and aged animals (left and middle columns); highly significant differences were detected between the two groups after the subsequent injection of RAC (P<0.001). (2B) Illustration of the evolution of the temporal phMRI response to dopaminergic challenges with APO followed by RAC in the putamen. Each time point represents the average value of ΔR₂* over a 5-minute period relative to the overall 15-minute baseline level; a, P<0.01 compared with normal healthy controls; b, P<0.01 compared with MPTP; c. P<0.01 MPTP vs. aged animals.

Figure 3

phMRI responses in the GPi. (3A) Similar pharmacological responses to either APO or the subsequent administration of dopamine receptor antagonists were found between MPTP-treated and aged animals. (3B) Illustration of the evolution of the temporal phMRI response to dopaminergic challenges with APO followed by either SCH or RAC in the GPi. Each time point represents the average value of ΔR₂* over a 5-minute period relative to the overall 15-minute baseline level. No statistically significant differences were found between groups. a, P<0.01 compared with normal healthy controls.

Figure 4

phMRI responses in the CD, GPe and SN. (4A) Significant (P<0.01) differences were found in the caudate between MPTP-treated and aged animals with APO and the subsequent administration of SCH (left and middle columns); (4B) Significant (P<0.01) differences were found in the GPe, between MPTP-treated and aged animals in responses to all dopaminergic stimulations i.e. strong activations were seen in the aged animals while much milder responses were seen in the MPTP-treated animals; (4C) In the SN, the only statistically significant differences were seen after the subsequent administration of SCH. Slight differences were also observed in responses to APO and the subsequent RAC, but they failed to reach statistically significant levels (left and right columns). a, P<0.01 compared with normal healthy controls; b, P<0.01 compared with MPTP.

Figure 5

Age- and parkinsonism-related changes in the basal ganglia. Compared with normal middle-aged animals, activity associated with dopaminergic stimulations were seen in the aged GPe and MPTP-treated striatum. Much smaller and/or no differences were observed between aged and MPTP-treated monkeys in the SN and GPi, respectively. The schematic diagram was modified based on Galvan and Wichmann (2008). Black arrows indicate inhibitory connections; gray arrows indicate excitatory connections. The thickness of the arrows corresponds to their presumed activity. Abbreviations: CM, centromedian nucleus of thalamus; CMA, cingulate motor area; Dir., direct pathway; D1, D2, dopamine receptor subtypes; Indir., indirect pathway; M1, primary motor cortex; Pf, parafascicular nucleus of the thalamus; PMC, premotor cortex; PPN, pedunculopontine nucleus; SMA, supplementary motor area. See text for other abbreviations.