The prediagnostic phase of Parkinson's disease

Abstract

The field of prediagnostic Parkinson's disease (PD) is fast moving with an expanding range of clinical and laboratory biomarkers, and multiple strategies seeking to discover those in the earliest stages or those 'at risk'. It is widely believed that the highest likelihood of securing neuroprotective benefit from drugs will be in these subjects, preceding current point of diagnosis of PD. In this review, we outline current knowledge of the prediagnostic phase of PD, including an up-to-date review of risk factors (genetic and environmental), their relative influence, and clinical features that occur prior to diagnosis. We discuss imaging markers across a range of modalities, and the emerging literature on fluid and peripheral tissue biomarkers. We then explore current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials, what we are learning from these initiatives, and how these studies will bring the field closer to realistically commencing primary or secondary preventive trials for PD. Further progress in this field hinges on greater clinical and biological description, and understanding of the prediagnostic, peridiagnostic and immediate postdiagnostic stages of PD. Identifying subjects 3-5 years before they are currently diagnosed may be an ideal group for neuroprotective trials. At the very least, these initiatives will help clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of disease.

Keywords: EPIDEMIOLOGY; MOVEMENT DISORDERS; PARKINSON'S DISEASE.

Figure 1

A schematic depicting normal (black solid line) and Parkinson's disease-related (grey solid line) nigral cell loss over time, including the point at diagnosis typically occurs (horizontal black hashed line) and the potential for modifying the trajectory of degeneration, if identified earlier (hashed grey line). NB. For colour version grey lines appear red, black lines remain black.

Figure 2

Risk factors and early features of Parkinson's disease associated with increased (or decreased) risk of subsequent diagnosis. Estimated magnitude of effect is plotted against estimated frequency. SN+ is hyperechogenicity in the region of the substantia nigra using transcranial sonography. Genetic and environmental risk factors are shown in lighter grey, and prediagnostic features and hyperechogenicity in darker grey. NB. For colour version genetic factors are red, environmental factors are orange, pre-diagnostic features are green and imaging features are blue.

Figure 3

A schematic showing determinants of risk, the prediagnostic phase (preclinical and prodromal phases) and clinical phase of Parkinson's disease, along with the parallel application of risk and disease progression markers to measure disease activity across phases.