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Examining Risk Factors, Prodromal Features of Parkinson Disease


Several known risk factors and prodromal features were associated with Parkinson disease, including traumatic brain injury and alcohol misuse, along with other comorbidities such as skin and gastrointestinal disorders.

A myriad of certain risk factors, comorbidities, and prodromal symptoms may be involved in the pathogenesis of Parkinson disease (PD), according to study findings published this week in JAMA Dermatology.

Prodromal features of PD have been indicated to potentially start more than a decade prior to the onset of typical clinical symptoms that inform diagnosis, such as tremor. Along with well-known genetic or environmental risk factors that are associated with PD development, other diagnoses such as type 2 diabetes or gastric diseases may increase the spread of pathology from the enteric nervous system via the vagal nerve to the central nervous system, researchers explained.

“There is increasing evidence for a number of possible risk factors that may predispose to the manifestation of the disease or facilitate development or spread of pathological lesions,” they added.

“The recognition of such risk factors and prodromal features of PD together with the presence of Lewy body pathology in peripheral organs and early extrastriatal brain pathology several years before PD diagnosis have widened our understanding of the development of the disease.”

In seeking to provide enhanced recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD, the study authors conducted a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance (covers 87% of all inhabitants of Germany) to analyze data over a 10-year period, between January 1, 2011, and December 31, 2020.

Patients with an incident diagnosis of PD, defined as the presence of an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic code in more than 1 insurance claim period (3 months), who did not have a previous diagnosis of parkinsonism or dementia in the preceding 3 years were included in the analysis. Patients with PD and controls were matched 1 to 2 for age, sex, region, and earliest year of outpatient encounter.

Data on selected exposures based on previous systematic reviews and case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of PD were collected for each ​​individual from general practice, both for each year and grouped for the periods less than 1 year, 2 to 4 years, and 5 to 10 years before index date, independent of calendar year and first onset.

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, of which 102,360 patients (74%) with PD and 27,652 controls (10%) were examined by a neurologist during the insurance quarter of diagnosis. 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 (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).

However, there was a reduced risk shown for nicotine misuse (OR, 0.92; 95% CI, 0.86-0.98) with PD.

Several other comorbidities and diagnoses were associated with later onset of PD:

  • 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)
  • Skin disorders, such as seborrheic dermatitis (OR, 1.30; 95% CI, 1.15-1.46) and psoriasis (OR, 1.13; 95% CI, 1.05-1.21), gastrointestinal disorders, such as gastroesophageal reflux (OR, 1.29; 95% CI, 1.25-1.33) and gastritis (OR, 1.28; 95% CI, 1.24-1.33), and conditions with a potential inflammatory component, including 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)
  • 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)

Regarding associations indicated 5 to 10 years before PD diagnosis, tremor (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) were noted.

The sole use of diagnoses made according to ICD-10 codes and not other electronic health care databases, such as The Health Improvement Network in the United Kingdom, was noted as a potential limitation of the findings. More subtle symptoms or features were also likely to have been underrecognized, noted researchers.

“These associations may reflect possible early extrastriatal and extracerebral pathology of PD due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD,” concluded the study authors. “Subtle associations require future testing in prospective controlled studies.”


Schrag A, Bohlken J, Dammertz L, et al. Widening the spectrum of risk factors, comorbidities, and prodromal features of Parkinson disease. JAMA Neurol. Published online November 7, 2022. doi:10.1001/jamaneurol.2022.3902

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