Prediagnostic presentations of Parkinson's disease in primary care: a case-control study

Background: Parkinson's disease has an insidious onset and is diagnosed when typical motor features occur. Several motor and non-motor features can occur before diagnosis, early in the disease process. We aimed to assess the association between first presentation of several prediagnostic features in primary care and a subsequent diagnosis of Parkinson's disease, and to chart the timeline of these first presentations before diagnosis.

Methods: We identified individuals with a first diagnosis of Parkinson's disease and those without Parkinson's disease from Jan 1, 1996, to Dec 31, 2012, from The Health Improvement Network UK primary care database. Codes were extracted for a range of possible prediagnostic or early symptoms, comprising motor features (tremor, rigidity, balance impairments, neck pain or stiffness, and shoulder pain or stiffness), autonomic features (constipation, hypotension, erectile dysfunction, urinary dysfunction, and dizziness), neuropsychiatric disturbances (memory problems, late-onset anxiety or depression, cognitive decline, and apathy), and additional features (fatigue, insomnia, anosmia, hypersalivation and rapid-eye-movement sleep behaviour disorder) in the years before diagnosis. We report the incidence of symptoms recorded in more than 1% of cases per 1000 person-years and incidence risk ratios (RRs) for individuals with and without Parkinson's disease at 2, 5, and 10 years before diagnosis.

Findings: 8166 individuals with and 46,755 individuals without Parkinson's disease were included in the study. Apathy, REM sleep behaviour disorder, anosmia, hypersalivation, and cognitive decline were all reported in less than 1% of people per 1000 person-years and were excluded from further analyses. At 2 years before Parkinson's disease diagnosis, the incidence of all studied prediagnostic features except neck pain or stiffness was higher in patients who went on to develop Parkinson's disease (n=7232) than in controls (n=40,541). At 5 years before diagnosis, compared with controls (n=25,544), patients who went on to develop Parkinson's disease (n=4769) had a higher incidence of tremor (RR 13·70, 95% CI 7·82-24·31), balance impairments (2·19, 1·09-4·16), constipation (2·24, 2·04-2·46), hypotension (3·23, 1·85-5·52), erectile dysfunction (1·30, 1·11-1·51), urinary dysfunction (1·96, 1·34-2·80), dizziness (1·99, 1·67-2·37), fatigue (1·56, 1·27-1·91), depression (1·76, 1·41-2·17), and anxiety (1·41, 1·09-1·79). At 10 years before diagnosis of Parkinson's disease, the incidence of tremor (RR 7·59, 95% CI 1·11-44·83) and constipation (2·01, 1·62-2·49) was higher in those who went on to develop Parkinson's disease (n=1680) than in controls (n=8305).

Interpretation: A range of prediagnostic features can be detected several years before diagnosis of Parkinson's disease in primary care. These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinson's disease.

Funding: Parkinson's UK.