Widening the Spectrum of Risk Factors, Comorbidities, and Prodromal Features of Parkinson Disease

JAMA Neurol. 2023 Feb 1;80(2):161-171. doi: 10.1001/jamaneurol.2022.3902.


Importance: The prodromal phase of Parkinson disease (PD) may last for more than 10 years. Recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD can increase understanding of the causes and development of the disease and help identify individuals at risk.

Objective: To identify the association of a subsequent diagnosis of PD with a range of risk factors and prodromal features, including lifestyle factors, comorbidities, and potential extracerebral manifestations of PD.

Design, setting, and participants: This was a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2011, and December 31, 2020. Included were patients with incident diagnosis of PD without a previous diagnosis of parkinsonism or dementia and controls matched 1:2 for age, sex, region, and earliest year of outpatient encounter.

Exposures: Exposures were selected based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of PD.

Main outcomes and measures: Previously postulated risk factors and prodromal features of PD, using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding.

Results: A total of 138 345 patients with incident PD (mean [SD] age, 75.1 [9.8] years; 73 720 male [53.3%]) and 276 690 matched controls (mean [SD] age, 75.1 (9.8) years; 147 440 male [53.3%]) were identified. Study participants were followed up for a mean (SD) of 6.0 (2.0) years. Consistent with previous reports, risk factors and prodromal features associated with PD included traumatic brain injury, odds ratio (OR), 1.62; 95% CI, 1.36-1.92; alcohol misuse, OR, 1.32; 95% CI, 1.21-1.44; hypertension, OR, 1.29; 95% CI, 1.26-1.31; anosmia, OR, 2.16; 95% CI, 1.59-2.93; and parasomnias (including RBD), OR, 1.62; 95% CI, 1.42-1.84. In addition, there were associations with restless legs syndrome (OR, 4.19; 95% CI, 3.91-4.50), sleep apnea (OR, 1.45; 95% CI, 1.37-1.54), epilepsy (OR, 2.26; 95% CI, 2.07-2.46), migraine (OR, 1.21; 95% CI, 1.12-1.29), bipolar disorder (OR, 3.81; 95% CI, 3.11-4.67), and schizophrenia (OR, 4.48; 95% CI, 3.82-5.25). The following diagnoses were also found to be associated with PD: sensory impairments beyond anosmia, such as hearing loss (OR, 1.14; 95% CI, 1.09-1.20) and changes of skin sensation (OR, 1.31; 95% CI, 1.21-1.43). There were also positive associations with skin disorders (eg, seborrheic dermatitis, OR, 1.30; 95% CI, 1.15-1.46; psoriasis, OR, 1.13; 95% CI, 1.05-1.21), gastrointestinal disorders (eg, gastroesophageal reflux, OR, 1.29; 95% CI, 1.25-1.33; gastritis, OR, 1.28; 95% CI, 1.24-1.33), conditions with a potential inflammatory component (eg, seronegative osteoarthritis, OR, 1.21; 95% CI, 1.03-1.43), and diabetes types 1 (OR, 1.32; 95% CI, 1.21-1.43) and 2 (OR, 1.24; 95% CI, 1.20-1.27). Associations even 5 to 10 years before diagnosis included tremor (odds ratio [OR], 4.49; 95% CI, 3.98-5.06), restless legs syndrome (OR, 3.73; 95% CI, 3.39-4.09), bipolar disorder (OR, 3.80; 95% CI, 2.82-5.14), and schizophrenia (OR, 4.00; 95% CI, 3.31-4.85).

Conclusions and relevance: Results of this case-control study suggest that the associations found between PD and certain risk factors, comorbidities, and prodromal symptoms in a representative population may reflect possible early extrastriatal and extracerebral pathology of PD. This may be due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.

MeSH terms

  • Aged
  • Anosmia
  • Case-Control Studies
  • Humans
  • Male
  • Parkinson Disease* / diagnosis
  • Prodromal Symptoms
  • Restless Legs Syndrome*
  • Risk Factors