Validations of apomorphine-induced BOLD activation correlations in hemiparkinsonian rhesus macaques

Abstract

Identification of Parkinson's disease at the earliest possible stage of the disease may provide the best opportunity for the use of disease modifying treatments. However, diagnosing the disease during the pre-symptomatic period remains an unmet goal. To that end, we used pharmacological MRI (phMRI) to assess the function of the cortico-basal ganglia circuit in a non-human primate model of dopamine deficiency to determine the possible relationships between phMRI signals with behavioral, neurochemical, and histological measurements. Animals with unilateral treatments with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), that expressed stable, long-term hemiparkinsonism were challenged with the dopaminergic receptor agonist, apomorphine, and structure-specific phMRI blood oxygen level-dependent (BOLD) activation responses were measured. Behavioral, histopathological, and neurochemical measurements were obtained and correlated with phMRI activation of structures of the cortico-basal ganglia system. Greater phMRI activations in the basal ganglia and cortex were associated with slower movement speed, decreased daytime activity, or more pronounced parkinsonian features. Animals showed decreased stimulus-evoked dopamine release in the putamen and substantia nigra pars compacta and lower basal glutamate levels in the motor cortex on the MPTP-lesioned hemisphere compared to the contralateral hemisphere. The altered neurochemistry was significantly correlated with phMRI signals in the motor cortex and putamen. Finally, greater phMRI activations in the caudate nucleus correlated with fewer tyrosine hydroxylase-positive (TH⁺) nigral cells and decreased TH⁺ fiber density in the putamen. These results reveal the correlation of phMRI signals with the severity of the motor deficits and pathophysiological changes in the cortico-basal ganglia circuit.

Keywords: Neurochemistry; Parkinson's disease; Pharmacological MRI; fMRI.

Fig. 1

phMRI activation in different structures between the MPTP-lesioned and unlesioned hemispheres. (A) caudate nucleus, (B) putamen, (C) primary motor cortex, and (D) substantia nigra (SN). *p < 0.05, ** p < 0.01.

Fig. 2

(A) Distance traveled between baseline and after MPTP lesion showed a significant (p < 0.001) decrease in distance traveled after MPTP lesion. (B) MPTP-treated animals showed characteristics associated with dopamine deficiency as measured with a parkinsonian rating scale. Long-term, stable parkinsonian features improved with apomorphine treatment; **P < 0.01. (C) Home cage activity was inversely correlated with phMRI signals in the right motor cortex. (D) Apomorphine-induced changes in the parkinsonian rating scale was positively correlated with BOLD activation in the right (MPTP-treated side) putamen.

Fig. 3

Areas of phMRI activation in the motor cortex and basal ganglia in (A) after a 20 min APO challenge. In the MPTP-lesioned side (), the putamen shows areas of higher APO-induced BOLD activation along the rostral-caudal axis than in the unlesioned side (). Sections were 3 mm in thickness through the putamen. *p < 0.05. (B) TH⁺ fiber density distribution along the anterior-posterior plane of the putamen in the MPTP-lesioned and the unlesioned hemispheres. (C) BOLD-responses in the right (MPTP-lesioned side) caudate were negatively correlated with the number of TH⁺ cells in the right substantia nigra. (D) BOLD-responses in the right motor cortex were negatively correlated with TH⁺ fibers in the right putamen.

Fig. 4

(A) Resting levels of glutamate were measured from 5 areas (2–3 mm apart) in the primary motor cortex from both the left and right hemispheres. Basal glutamate levels in the ipsilateral motor cortex were significantly lower than the contralateral motor cortex; P = 0.031. K+ (100 mM)- and amphetamine (250 μM)-evoked DA release was significantly attenuated in the ipsilateral (B) putamen (Put) and (C) SNc; ***P < 0.0001 – adapted from (Quintero et al., 2011). (D) Glutamate levels in the right (MTP-lesioned side) motor cortex were inversely correlated with phMRI signals in the right putamen. (E) BOLD-responses in the right motor cortex were negatively correlated with dopamine levels in the right subtantia nigra after amphetamine stimulation.