REM sleep behavior disorder, mild cognitive impairment, and orthostatic hypotension stood out among 9 nonmotor features documented before Parkinson disease diagnosis in a large US electronic health record analysis, with REM sleep behavior disorder showing the strongest association with subsequent Parkinson disease diagnosis.
The findings, published in npj Parkinson’s Disease, showed that all 3 features remained consistently associated with Parkinson disease (PD) across multiple sensitivity analyses, whereas associations with depression and anxiety were less consistent.
Researchers conducted a retrospective matched case-control study using the National Institutes of Health All of Us Research Program Registered Tier dataset. The analysis included 2,673 patients aged 40 years or older with at least 2 distinct PD diagnosis dates and 10,692 controls without PD, matched 4:1 by sex and year of birth within 2 years. Mean age was 66.8 years among cases and 66.7 years among controls, and 61.2% of both groups were male. Researchers examined 9 nonmotor features documented before the first recorded PD diagnosis: REM sleep behavior disorder, mild cognitive impairment, orthostatic hypotension, constipation, urinary dysfunction, depression, anxiety, insomnia, and erectile dysfunction.
REM sleep behavior disorder was documented in 2.7% of patients with PD versus 0.2% of controls and was associated with nearly 10-fold higher odds of PD. The finding was based on 71 cases and 24 controls with documented REM sleep behavior disorder, and researchers noted that the condition remains substantially underdocumented in routine care. Mild cognitive impairment was documented in 4.8% of cases versus 0.9% of controls and was associated with approximately 4-fold higher odds. Orthostatic hypotension was documented in 5.6% versus 2.2% and was associated with 83% higher primary conditional odds and 88% higher age- and sex-adjusted unconditional odds.
Researchers reported that associations for all 3 features remained stable across sensitivity analyses using stricter case definitions, different ascertainment windows, and several exclusion criteria.
Depression was the most frequently documented feature, occurring before PD diagnosis in 31.1% of cases versus 21.6% of controls. Anxiety was documented in 28.5% versus 19.9%, urinary dysfunction in 18.0% versus 12.3%, and constipation in 16.8% versus 10.8%. Each showed a modest association with PD in the primary analysis, whereas insomnia was not associated.
When researchers restricted the analysis to 1,839 patients with recorded levodopa or carbidopa exposure and their matched controls, the associations with REM sleep behavior disorder, mild cognitive impairment, and orthostatic hypotension remained. Depression and anxiety were no longer statistically significant. Researchers characterized the depression and anxiety findings as the least secure of the positive associations.
The timing of first documentation also varied. REM sleep behavior disorder was first recorded a median of 1.07 years before PD diagnosis, mild cognitive impairment 1.42 years before diagnosis, and orthostatic hypotension 2.83 years beforehand. Depression was documented a median of 5.20 years before diagnosis. Researchers cautioned that these intervals reflect electronic health record documentation rather than biological onset and should not be interpreted as the true duration of the prodromal period.
The overall model had modest discrimination, with an area under the curve of 0.585. Researchers noted that electronic health record–documented nonmotor features were informative at the group level but were insufficient as a standalone tool for predicting PD in individual patients.
The authors reported no competing interests and no dedicated funding for the study. They also disclosed that generative AI (Claude, Anthropic) was used to assist with statistical code development and review as well as manuscript drafting and editing; the authors performed and verified the study design, data extraction, statistical analyses, and interpretation.
Source: npj Parkinson’s Disease
