Molecular Imaging in Parkinsonian Disorders—What’s New and Hot?

HIGHLIGHTS: Imaging of the dopamine transporter (DAT) (in particular using 11C- or 18F-PE2I) most reliably and precisely measures neurodegeneration of the dopaminergic system in parkinsonian disorders and its progression in longitudinal studies. Combining DAT imaging and iron- and neuromelanin-sensitive MR imaging in vivo unveiled the sequential progression of neurodegeneration along the sensorimotor, associative, and limbic territories in the striatum followed by the substantia nigra in Parkinson’s disease. DAT imaging is the most accurate marker for prodromal PD and predicts phenoconversion to clinical motor symptoms in patients with REM-sleep behavior disorders (RBD). Dopaminergic imaging can be used to investigate motor reserve in PD patients. Peripheral molecular imaging shows that autonomous denervation of the heart and gut in prodromal and de novo PD with RBD precedes striatal dopaminergic loss, thereby supporting peripheral starting points in those patients. Serotonergic denervation in the subcortical and cortical limbic regions is associated with apathy, depression, and anxiety in PD. Noradrenergic terminals loss plays a critical role in RBD and was shown to exceed locus coeruleus pathology in PD using 11C-MeNER PET. Cholinergic imaging is now complemented by the new PET tracer 18F-FEOBV, which binds to presynaptic transporters, particularly in subcortical structures. Dual-phase dynamic PET imaging may enable to inform both metabolic and molecular disease-related patterns with a single injection, including tracers for DAT or tau. Using 11C-UCB-J, prominent loss of synaptic density in the substantia nigra and brainstem was demonstrated in PD, even in the early stage, extending to the cortex in DLB, as well as PSP and CBD. Tau imaging using second-generation tracers with increased specificity greatly improved the diagnosis of tau aggregation in PSP and CBD. Despite recent advances and promising results in MSA patients using 18F-ACI12589 PET, no tracer is readily available to image α-synuclein aggregates in vivo in parkinsonian disorders. Computational modeling of tracer affinity in silico, coupled with cryogenic electron microscopy will improve efficiency and accelerate the development of novel tracers. ABSTRACT: Neurodegenerative parkinsonian disorders are characterized by a great diversity of clinical symptoms and underlying neuropathology, yet differential diagnosis during lifetime remains probabilistic. Molecular imaging is a powerful method to detect pathological changes in vivo on a cellular and molecular level with high specificity. Thereby, molecular imaging enables to investigate functional changes and pathological hallmarks in neurodegenerative disorders, thus allowing to better differentiate between different forms of degenerative parkinsonism, improve the accuracy of the clinical diagnosis and disentangle the pathophysiology of disease-related symptoms. The past decade led to significant progress in the field of molecular imaging, including the development of multiple new and promising radioactive tracers for single photon emission computed tomography (SPECT) and positron emission tomography (PET) as well as novel analytical methods. Here, we review the most recent advances in molecular imaging for the diagnosis, prognosis, and mechanistic understanding of parkinsonian disorders. First, advances in imaging of neurotransmission abnormalities, metabolism, synaptic density, inflammation, and pathological protein aggregation are reviewed, highlighting our renewed understanding regarding the multiplicity of neurodegenerative processes involved in parkinsonian disorders. Consequently, we review the role of molecular imaging in the context of disease-modifying interventions to follow neurodegeneration, ensure stratification, and target engagement in clinical trials.