The clinical heterogeneity of Parkinson's disease and its therapeutic implications

Although Parkinson's disease (PD) is primarily a movement disorder, there are a range of associated nonmotor symptoms, including cognitive impairment, depression and sleep disturbance. These can occur throughout the disease course, even predating the motor syndrome. However, both motor and nonmotor symptoms are variable between individual patients. Rate of disease progression is also heterogenous: although 50% have reached key milestones of either postural instability or dementia within 4 years from diagnosis, almost a quarter have a good prognosis at 10 years. In this review we discuss how a range of different factors including clinical features, pathology and genetics, have been used to describe the heterogeneity of PD. We explore the value of longitudinal studies of incident PD cohorts, based on our own experience in Cambridgeshire, to define differences in rates of disease progression and predictors of outcome, including how such studies have informed the development of prognostic models which can be used at an individual patient level. Finally, we discuss the benefits of better understanding the basis of heterogeneity of PD in terms of implications for the development and trialling of more targeted therapies for different subgroups of patients, including regenerative approaches.