Translational molecular imaging and drug development in Parkinson’s disease

Molecular Neurodegeneration

Review

Nehal H. Elghazawy¹  Alyaa Dawood¹  Thomas Wichmann²  Catherine Gebhard³  Ahmed Haider⁴  Steven H. Liang⁴  Wolfgang Sippl⁵  Ernest Arenas⁶  Marius Hoener⁷ 

[1]Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al-Tagamoa Al-Khames, 11835, Cairo, Egypt

[2]Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance of Al-Tagamoa Al-Khames, 11835, Cairo, Egypt

[3]Department of Neurology/School of Medicine, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

[4]Department of Nuclear Medicine, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland

[5]Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

[6]Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, 02114, Boston, MA, USA

[7]Department of Radiology and Imaging Sciences, Emory University, 101 Woodruff Circle, 30322, Atlanta, GA, USA

[8]Institute of Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, W.-Langenbeck-Str. 4, 06120, Halle, Germany

[9]Karolinska Institutet, MBB, Molecular Neurobiology, Stockholm, Sweden

[10]Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070, Basel, Switzerland

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

DOI  :  10.1186/s13024-023-00600-z

 received in 2022-10-10, accepted in 2023-01-23,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2023