New Data Point to Range of Comorbidities, Symptoms of Parkinson Disease Years Before Diagnosis

In the main matched analysis, associated noted before Parkinson disease diagnosis were motor (up to 10 years) and cognitive (up to 5 years) symptoms.

Research from a nested case-control study of a diverse, urban-dwelling population with universal access to healthcare identified a range of comorbidities and symptoms encountered years before Parkinson disease (PD) diagnosis. Tremor and memory symptoms, observed as early as 10 and 5 years before diagnosis, respectively, had the highest associations with subsequent PD.1

"We believe our findings raise potentially important practical considerations for primary care physicians and the opportunity to address patient concerns at an earlier stage of the disease,” lead investigator Christina Simonet, MD, PhD student, Queen Mary University of London, and colleagues wrote. “It is not a case of screening for asymptomatic disease but correctly identifying the underlying cause in patients who are presenting with symptoms and may seek timely onward referral."

In this nested case-control study, investigators aimed to understand the association between risk factors and prediagnostic presentations of PD in an ethnically diverse UK population with high socioeconomic deprivation that counters traditional PD studies which largely encompassed White patients. Based on the 2011 UK Census, London had the greatest ethnic diversity of anywhere in the UK, with the highest proportion of Black, South Asian, and mixed/other ethnic groups, which comprised approximately 45% of residents in East London compared with 14% of the rest of the UK.

To do so, Simonet et al analyzed electronic health records of 1055 patients with PD and 1,009,523 controls from 1990 to 2018. They conducted a main matched analysis and unmatched analysis adjusted for age and sex. Three time periods (<2, 2 to <5, and 5-10 years before diagnosis) were analyzed separately and together. Demographically, they found that patients with PD were more likely to be older vs controls (mean age, 72.9 years [SD, 11.3] vs 40.3 years [15.2]) and more patients were male (632 [59.9%] vs 516,862 [51.2%]).

In the matched analysis, 52 (4.9%) patients who were subsequently diagnosed with PD presented with memory symptoms compared with less than 1% of controls. Within 2 years of PD diagnosis, individuals with memory symptoms had an approximate 9-fold increased odds of developing the neurodegenerative disorder (odds ratio [OR], 8.60; 95% CI, 5.91-12.49). This association was also observed up to 5 years before diagnosis (2 to <5 years: OR, 3.08; 95% CI, 1.81-5.24) but not further (5-10 years: OR, 2.06; 95% CI, 0.96-4.42).

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Investigators identified 7-fold increased odds of receiving a PD diagnosis within 2 years (OR, 6.84; 95% CI, 3.38-13.85) among patients with hypotension. Although not as pronounced, this association was also observed in the 2 to less than 5 years before diagnosis time period (OR, 4.88; 95% CI, 2.44-9.77). Constipation, more commonly found in patients with PD (4% vs 1%), was associated with a 3-fold increase in subsequent diagnosis and was significant across all 3 analysis periods. In contrast with other autonomic symptoms, an association between erectile dysfunction and future PD in men was observed only 5 to 10 years before diagnosis (OR, 1.51; 95% CI, 1.11-2.05).

Odds of subsequent PD were increased in those who had hypertension (OR, 1.29; 95% CI, 1.07-1.56) or type 2 diabetes (OR, 1.41; 95% CI, 1.09-1.82) 5 to 10 years before diagnosis, but not closer in time to diagnosis. Contrary to being overweight, which had no association with subsequent PD diagnosis, investigators found that being underweight in the period closest to PD diagnosis was associated with higher odds of developing the disease (OR, 2.73; 95% CI, 1.17-6.37).

Epilepsy and hearing loss, 2 factors which the investigators noted had been largely underreported in the literature, were associated with subsequent PD diagnosis over the 3 time periods (ORs for epilepsy: approximately 3; ORs for hearing loss: approximately 1.2), except for hearing loss in the period closer to PD diagnosis (OR, 1.03; 95% CI, 0.69-1.52).

Simonet et al noted that epilepsy occurring before PD was a "notable finding," although some evidence for the association had been identified in previous studies. "In the present study, drug-induced parkinsonism could not be ruled out owing to the lack of information about medication," they wrote. "Certain antiepileptic drugs have been associated with tremor and PD, and coexisting vascular disease might also plausibly link epilepsy with PD, especially in the older population. Further research is needed to investigate a potential link."

Shoulder pain was associated with a doubling of the odds of PD diagnosis up to 5 years before diagnosis (<2 years: OR, 2.23 [95% CI, 1.50-3.30]; 2 to <5 years: OR, 1.88 [95% CI, 1.33-2.66]), whereas neck pain was not associated with PD across the 3 periods.

The associations of midlife comorbidities, nonmotor manifestations, and early motor markers were all fairly consistent when stratified by ethnic group. Notably, epilepsy was associated with subsequent PD in patients who were Black or White but not in those of South Asian ethnicity. Rigidity was not reported in Black patients before diagnosis and had lower ORs in South Asian patients (OR, 4.62; 95% CI, 0.63-33.88).

1. Simonet C, Bestwick J, Jitlal M, et al. Assessment of risk factors and early presentations of Parkinson disease in primary care in a diverse UK population. JAMA Neurol. 2022;79(4):359-369. doi:10.1001/jamaneurol.2022.0003