The Concept of Prodromal Parkinson's Disease

Abstract

Parkinson's disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific pathology prior to appearance of these classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to identify and validate markers for the preclinical and prodromal stages of the illness. Currently, several nonmotor symptoms have been associated with an increased risk to develop PD in otherwise healthy individuals and ongoing research is aimed at validating a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. In fact, the recently defined MDS research criteria for prodromal PD have included combinations of risk and prodromal markers allowing to define target populations of future disease modification trials.

Keywords: Parkinson’s disease (PD); biomarker; early diagnosis; genetic and molecular biomarkers; neuroimaging; nonmotor symptoms (NMS); premotor PD.

Fig.1

Midbrain / substantia nigra (SN) imaging with magnetic resonance imaging (MRI) and Transcranial sonography (TCS). A: Susceptibility weighted (SWI) MRI image of a healthy control (HC) at the left column, demonstrating the magnified dorsolateral nigral hyperintensity within the right SN. White arrows mark the dorsolateral nigral hyperintensity in the survey as well as in the magnified illustration. The right column show SWI images of a patient with Parkinson’s disease (PD), demonstrating the absence of the dorsolateral nigral hyperintensity. B: TCS images of mesencaphalic scanning planes showing typically butterfly-shaped mesencephalic brainstems from a HC with a normal midbrain echogenicity in the upper images. A PD patient with an enlarged midbrain echogenicity at the area of the SN (SN-hyperechogenicity) is shown in the lower images.