Non-motor symptoms of Parkinson’s disease: the submerged part of the iceberg

James Parkinson, a physician from London, described the «shaking palsy» now known as Parkinson’s disease (PD) in his classic essay in 1817. Parkinson noted tremor, bradykinesia, rigidity and stooped posture as the key motor features of this condition but also drew attention to sleep dysfunction, delirium, dementia, and dysautonomia, now known to be non-motor symptoms (NMS) of PD. Inspite of their importance, NMS in PD still remain under-recognised and poorly studied. Description of neuropathological correlates of NMS, as well as the development of comprehensive tools for their assessment in the early 2000’s, such as the NMS questionnaire (NMSQuest) and scale (NMSS), helped to establish the importance of NMS in PD and their crucial link with quality of life. In many countries, NMS evaluation in PD is now a part of the good clinical practice standards. Studies of the integral role of NMS in PD clinical structure and natural history of PD led to the concept of PD as a complex combination of motor and non-motor manifestations with a long prodromal phase dominated by a number of NMS. The prodromal phase of PD is a major current research topic: NMS-associated biomarkers may help to identify subjects who are at risk of developing motor-phase PD and, potentially, are candidates for neuroprotective therapies. NMS burden grading with cut off values, which can be used as outcome measure in clinical trials in patients with PD, have been validated. The complex multi-neurotransmitter dysfunction of PD has been reported to manifest clinically as difeferent non-motor subtypes. Recognition of such subtypes may lead to the emergence of personalized and precision medicine approaches in PD.