In vivo imaging markers for the characterization of molecular changes in Parkinson and Huntington's disease

Abstract

Parkinson’s disease (PD) and Huntington’s disease (HD) are neurodegenerative disorders characterized by a progressive multi-systemic accumulation of misfolded proteins associated with neuronal dysfunction and neuronal loss. The rationale of this thesis is to examine, by means ofthe state of the art Positron emission tomography (PET) methodology combined with the use of high resolution MRI image molecular changes associated to the early stages of PD and HD. PET is a molecular imaging technique that, due to recent advancements in terms ofradioligand development and PET instrumentation, such as the high-resolution research tomograph (HRRT) and PET quantification, may contribute to examine in vivo the distribution and availability of different biochemical targets. The work included in the thesis can be subdivided into two projects.

The first project is dedicated to PD and to the study of two relevant molecular targets (dopamine and serotonin transporters), examined respectively with the radioligands [18F]FEPE2I and [11C]MADAM. In paper I, it is shown that [18F]FE-PE2I represents a reliable imaging biomarker to study the dopamine transporter (DAT) in the striatum and in the substantia nigra in PD. In paper II, a validation of a new approach to examine the serotonin transporter protein in small brainstem structures is presented. In paper III, [18F]FE-PE2I was used to study the entire nigro-striatal dopaminergic system, including dopamine projections, in a larger group of PD patients. The study was able to show a prominent involvement of the dopamine transporter in the striatum, a relatively milder reduction of DAT in the substantia nigra and a relative preservation of the protein along the nigro-striatal projections.

The second project is dedicated to the evaluation of Phosphodiesterase 10A as new molecular target for HD. This project includes two studies in which the radioligand [18F]MNI-659 has been used as radioligand for PDE10A and the D2/3 receptors radioligand [11C]raclopride that has been used as internal reference. In paper IV, it is shown that aging is associated with a considerable reduction of PDE10A. In Paper V, the same targets are examined in selected cohorts of HD subjects in pre-manifest and manifest stages. The study shows that PDE10A was preserved in early pre-manifest HD subjects and progressively decreased in late premanifest and manifest HD stages.

In conclusion the presented applications of new PET molecular imaging probes provided relevant information that contributes to measure early changes of molecular targets associated with the onset and progression of neuronal loss occurring in PD and HD.