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. While 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, three groups of rhesus macaques were studied: Normal middle-aged animals (used as controls), middle-aged animals with MPTP-induced parkinsonism, and aged animals (>20 years old) with declines in motor function. All animals underwent the same behavioral and phMRI procedures to measure changes in basal ganglia function in response to dopaminergic drug challenges consisting of apomorphine (APO) administration followed by either a D1 (SCH23390) or 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 two groups in the internal segment of the globus pallidus (GPi). In contrast, the pharmacological responses seen in the control animals were much milder compared with the other two groups in all 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.

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

“…The results from our study in middle-aged rhesus monkeys with stable, long-term parkinsonism caused by MPTP administration confirm a close relationship between BOLD activation in the cortico-nigrostriatal loops induced by dopaminergic receptor stimulation and the severity of parkinsonism. In addition, BOLD activation was seen to correlate with 1) cortical levels of resting glutamate, 2) nigrostriatal dopamine overflow, and 3) histopathologically-determined numbers of dopaminergic neurons and terminals The results are in line with our previous studies that showed phMRI BOLD-responses induced by dopaminergic drugs can be used for assessing nigrostriatal dopamine function(Zhang et al, 2006), and for differentiating PD-related from age-related changes in basal ganglia function (Andersen et al, 2015). Future studies will need to be carried out to advance the development of this imaging strategy for application in humans.…”

“…As an imaging modality, phMRI has a number of advantages related to molecular, structural, and functional neuroimaging that are rapidly expanding the neurobiological understanding of the complexities of PD. phMRI holds the promise of providing early indications of the pharmacodynamic activity of novel CNS-targeted compounds in a safe, non-invasive manner through blood oxygenation level dependent (BOLD) imaging in experimental animals (Andersen et al, 2015; Zhang et al, 2018), and in humans (Barber et al, 2017; Nemoto et al, 2017). As a result, significant effort has been devoted to implementing phMRI as a translational research tool to develop novel CNS compounds (Bifone and Gozzi, 2012; Wise and Tracey, 2006) and to study neurological disorders (Andersen et al, 2015; Seibyl et al, 2012; Weiller et al, 2006).…”

“…phMRI holds the promise of providing early indications of the pharmacodynamic activity of novel CNS-targeted compounds in a safe, non-invasive manner through blood oxygenation level dependent (BOLD) imaging in experimental animals (Andersen et al, 2015; Zhang et al, 2018), and in humans (Barber et al, 2017; Nemoto et al, 2017). As a result, significant effort has been devoted to implementing phMRI as a translational research tool to develop novel CNS compounds (Bifone and Gozzi, 2012; Wise and Tracey, 2006) and to study neurological disorders (Andersen et al, 2015; Seibyl et al, 2012; Weiller et al, 2006). Drug-induced pharmacodynamic responses detected from alterations in BOLD signals or relative cerebral blood volume/flow (rCBV/rCBF) can serve as imaging biomarkers to delineate the central effect of drug actions (Bhattacharyya et al, 2017; Ghariq et al, 2014; Jann et al, 2015; Tak et al, 2015).…”

How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

“…High 3 T MR imaging demonstrated iron deposition and microstructural changes in humans exposed to paraquat [76], a pesticide used to induce parkinsonism in rodents, findings routinely reported in other animal models of PD and in PD patients [37]. The use of Bpharmacologic MRI^to support clinical diagnosis has been validated in well-characterized animal models [2]. A recent study in parkinsonian marmosets [26] combining in vivo diffusion tensor imaging (DTI) and microscopic tractography has supported the use of DTI as a diagnostic tool in PD.…”

Functional Imaging and Physiological Modulation with Acupuncture in Parkinson’s Disease and Nonhuman Primate Models of Dopamine Dysfunction

“…Furthermore, phMRI has been used to monitor other treatments associated with PD in a preclinical, translational study [11]. The utility of fMRI/phMRI has even been extended to differentiate dysfunction in the basal ganglia between parkinsonian and aged monkeys [12]. Based on those clinical and preclinical studies, these imaging modalities have the possibility to help untangle the underlying neural mechanisms of acupuncture.…”