Translational molecular imaging and drug development in Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects elderly people and constitutes a major source of disability worldwide. Notably, the neuropathological hallmarks of PD include nigrostriatal loss and the formation of intracellular inclusion bodies containing misfolded α-synuclein protein aggregates. Cardinal motor symptoms, which include tremor, rigidity and bradykinesia, can effectively be managed with dopaminergic therapy for years following symptom onset. Nonetheless, patients ultimately develop symptoms that no longer fully respond to dopaminergic treatment. Attempts to discover disease-modifying agents have increasingly been supported by translational molecular imaging concepts, targeting the most prominent pathological hallmark of PD, α-synuclein accumulation, as well as other molecular pathways that contribute to the pathophysiology of PD. Indeed, molecular imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be leveraged to study parkinsonism not only in animal models but also in living patients. For instance, mitochondrial dysfunction can be assessed with probes that target the mitochondrial complex I (MC-I), while nigrostriatal degeneration is typically evaluated with probes designed to non-invasively quantify dopaminergic nerve loss. In addition to dopaminergic imaging, serotonin transporter and N-methyl-D-aspartate (NMDA) receptor probes are increasingly used as research tools to better understand the complexity of neurotransmitter dysregulation in PD. Non-invasive quantification of neuroinflammatory processes is mainly conducted by targeting the translocator protein 18 kDa (TSPO) on activated microglia using established imaging agents. Despite the overwhelming involvement of the brain and brainstem, the pathophysiology of PD is not restricted to the central nervous system (CNS). In fact, PD also affects various peripheral organs such as the heart and gastrointestinal tract - primarily via autonomic dysfunction. As such, research into peripheral biomarkers has taken advantage of cardiac autonomic denervation in PD, allowing the differential diagnosis between PD and multiple system atrophy with probes that visualize sympathetic nerve terminals in the myocardium. Further, α-synuclein has recently gained attention as a potential peripheral biomarker in PD. This review discusses breakthrough discoveries that have led to the contemporary molecular concepts of PD pathophysiology and how they can be harnessed to develop effective imaging probes and therapeutic agents. Further, we will shed light on potential future trends, thereby focusing on potential novel diagnostic tracers and disease-modifying therapeutic interventions.

Keywords: Dopamine; Drug development; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Translational molecular imaging; α-Synuclein.

Fig. 1

Clinical presentation, pathophysiology and diagnostic imaging in Parkinson’s disease (PD). A Cardinal motor symptoms and non-motor features of PD. B Pathological hallmarks of PD include aggregates of misfolded α-synuclein (Lewy bodies), mitochondrial dysfunction & oxidative stress, infiltration of immune cells and persistent activation of microglia, as well as an increased release of cytokines. The pathophysiology of PD prompts neurodegeneration and dopamine deficiency, which is particularly pronounced in the mammalian striatum. C Translational molecular imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT), visualizing striatal degeneration in PD non-invasively. DAT, dopamine transporter.; DDC, DOPA decarboxylase; VMAT2, vesicular monoamine transporter 2. Figure 1C reprinted by permission from the Royal College of Physicians (RCP): Pagano et al., [17] copyright (2016)

Fig. 2

Molecular imaging in Parkinson’s disease (PD). Selected biological targets that have been harnessed for positron emission tomography (PET) and single photon-emission tomography (SPECT) imaging in PD. These targets have been used to allow diagnostic imaging as well as to facilitate drug discovery & development and include the translocator protein 18 kDa (TSPO), which is upregulated in activated microglia, mitochondrial complex I (MC-I) to assess mitochondrial function, various α-synuclein and amyloid-β (Aβ)-targeted probes, radiolabeled dopamine & serotonin transporter substrates & ligands of dopamine receptors, probes targeting the vesicular monoamine transporter 2 (VMAT2) and attempts to visualize autophagy as well as cytokines such as the tumor necrosis factor α (TNF-α). Given that these molecular variables are critical to the pathophysiology of PD, most of them have been suggested as therapeutic targets

Fig. 3

Established vs. experimental therapies in Parkinson’s disease (PD). While current drug PD therapy is primarily symptomatic and attempts to restore dopaminergic function, many lines of experimental research focus currently on the development of potentially disease-modifying concepts. The latter involve various targets that can be visualized using translational molecular imaging probes, thus providing the opportunity to conduct imaging-guided preclinical and clinical studies in PD. Among the promising concepts, preventing the formation of inclusion bodies by targeting misfolded α-synuclein, attenuating neuroinflammation via anti-tumor necrosis factor α (TNF-α) antibodies and glucagon-like peptide 1 (GLP-1) activation, as well as stimulation of autophagy with leucine-rich repeat kinase 2 (LRRK2) inhibitors have been suggested